Author: "Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]" - Searchworks@Jio Institute Digital Library Search Results

Your search keyword '"Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]"' showing total 69 results

Start Over Author "Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]"

69 results on '"Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]"'

1. The Amyotrophic Lateral Sclerosis M114T PFN1 Mutation Deregulates Alternative Autophagy Pathways and Mitochondrial Homeostasis

Author: Elisa Teyssou, Laura Chartier, Delphine Roussel, Nirma D. Perera, Ivan Nemazanyy, Dominique Langui, Mélanie Albert, Thierry Larmonier, Safaa Saker, François Salachas, Pierre-François Pradat, Vincent Meininger, Philippe Ravassard, Francine Côté, Christian S. Lobsiger, Séverine Boillée, Bradley J. Turner, Danielle Seilhean, Stéphanie Millecamps, MILLECAMPS, Stéphanie, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Structure Fédérative de Recherche Necker (SFR Necker - UMS 3633 / US24), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Banque d’ADN et de Cellules, Généthon, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Biomédicale (LIB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), University of Ulster, Hôpital privé des Peupliers (Paris), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: lymphoblasts, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, ALS, genetics, mutations, alternative autophagy, RAB9, mitochondrial homeostasis, post-mortem spinal cord, transgenic mice, NSC-34 cell line, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Catalysis, Inorganic Chemistry, Mice, Profilins, Autophagy, Animals, Homeostasis, Humans, Physical and Theoretical Chemistry, Molecular Biology, Spectroscopy, Organic Chemistry, Amyotrophic Lateral Sclerosis, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, General Medicine, Computer Science Applications, Mitochondria, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, rab GTP-Binding Proteins, Mutation
Abstract: International audience; Mutations in profilin 1 (PFN1) have been identified in rare familial cases of Amyotrophic Lateral Sclerosis (ALS). PFN1 is involved in multiple pathways that could intervene in ALS pathology. However, the specific pathogenic role of PFN1 mutations in ALS is still not fully understood. We hypothesized that PFN1 could play a role in regulating autophagy pathways and that PFN1 mutations could disrupt this function. We used patient cells (lymphoblasts) or tissue (post-mortem) carrying PFN1 mutations (M114T and E117G), and designed experimental models expressing wild-type or mutant PFN1 (cell lines and novel PFN1 mice established by lentiviral transgenesis) to study the effects of PFN1 mutations on autophagic pathway markers. We observed no accumulation of PFN1 in the spinal cord of one E117G mutation carrier. Moreover, in patient lymphoblasts and transfected cell lines, the M114T mutant PFN1 protein was unstable and deregulated the RAB9-mediated alternative autophagy pathway involved in the clearance of damaged mitochondria. In vivo, motor neurons expressing M114T mutant PFN1 showed mitochondrial abnormalities. Our results demonstrate that the M114T PFN1 mutation is more deleterious than the E117G variant in patient cells and experimental models and suggest a role for the RAB9-dependent autophagic pathway in ALS.
Published: 2022
Full Text: View/download PDF

2. Alterations of neuronal lysosomes in Alzheimer's disease and in APPxPS1-KI mice

Author: Androuin, Alexandre, Thierry, Manon, Boluda, Susana, Baskaran, Asha, Langui, Dominique, Duyckaerts, Charles, Potier, Marie-Claude, El Hachimi, Khalid Hamid, Delatour, Benoît, Marty, Serge, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Marty, Serge
Subjects: Neurons, Amyloid beta-Peptides, electron microscopy, General Neuroscience, [SDV]Life Sciences [q-bio], Mice, Transgenic, General Medicine, amyloid-β, Lipofuscin, [SDV] Life Sciences [q-bio], Psychiatry and Mental health, Clinical Psychology, Amyloid beta-Protein Precursor, Disease Models, Animal, Mice, Alzheimer Disease, lysosome, Animals, Humans, Geriatrics and Gerontology, Lysosomes, Alzheimer’s disease
Abstract: International audience; Background: The cellular and molecular alterations associated with synapse and neuron loss in Alzheimer's disease (AD) remain unclear. In transgenic mouse models that express mutations responsible for familial AD, neuronal and synaptic losses occur in populations that accumulate fibrillar amyloid-β 42 (Aβ42) intracellularly.Objective: We aimed to study the subcellular localization of these fibrillar accumulations and whether such intraneuronal assemblies could be observed in the human pathology.Methods: We used immunolabeling and various electron microscopy techniques on APP x presenilin1 - knock-in mice and on human cortical biopsies and postmortem samples.Results: We found an accumulation of Aβ fibrils in lipofuscin granule-like organelles in APP x presenilin1 - knock-in mice. Electron microscopy of human cortical biopsies also showed an accumulation of undigested material in enlarged lipofuscin granules in neurons from AD compared to age-matched non-AD patients. However, in those biopsies or in postmortem samples we could not detect intraneuronal accumulations of Aβ fibrils, neither in the lipofuscin granules nor in other intraneuronal compartments.Conclusion: The intralysosomal accumulation of Aβ fibrils in specific neuronal populations in APPxPS1-KI mice likely results from a high concentration of Aβ42 in the endosome-lysosome system due to the high expression of the transgene in these neurons.
Published: 2022

3. Visual deep learning-based explanation for neuritic plaques segmentation in Alzheimer's Disease using weakly annotated whole slide histopathological images

Author: Gabriel Jimenez, Anuradha Kar, Mehdi Ounissi, Léa Ingrassia, Susana Boluda, Benoît Delatour, Lev Stimmer, Daniel Racoceanu, Delatour, Benoît, Linwei Wang, Qi Dou, P. Thomas Fletcher, Stefanie Speidel, Shuo Li, Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Sorbonne Université (SU)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Reproduction et développement des plantes (RDP), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), This research was supported by Mr Jean-Paul Baudecroux and The Big Brain Theory Program - Paris Brain Institute (ICM). The human samples were obtained from the Neuro-CEB brain bank (https://www.neuroceb.org/en/) (BRIF Number 0033-00011), partly funded by the patients’ associations ARSEP, ARSLA, 'Connaître les Syndromes Cérébelleux', France-DFT, France Parkinson and by Vaincre Alzheimer Fondation, to which we express our gratitude. We are also grateful to the patients and their families., École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and This research was supported by Mr Jean-Paul Baudecroux and The Big Brain Theory Program - Paris Brain Institute (ICM). The human samples were obtained from the Neuro-CEB brain bank (https://www.neuroceb.org/en/) (BRIF Number 0033-00011), partly funded by the patients’ associations ARSEP, ARSLA, 'Connaître les Syndromes Cérébelleux', France-DFT, France Parkinson and by Vaincre Alzheimer Fondation, to which we express our gratitude. We are also grateful to the patients and their families. This work was granted access to the HPC resources of IDRIS under the allocation 2022-AD011013250 made by GENCI.
Subjects: FOS: Computer and information sciences, [INFO.INFO-AI] Computer Science [cs]/Artificial Intelligence [cs.AI], Computer Science - Machine Learning, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Image and Video Processing (eess.IV), Tau aggregates, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Electrical Engineering and Systems Science - Image and Video Processing, Neuritic Plaques, Alzheimer's Disease, Machine Learning (cs.LG), [INFO.INFO-AI]Computer Science [cs]/Artificial Intelligence [cs.AI], Deep Learning, Segmentation, Visual explanation, FOS: Electrical engineering, electronic engineering, information engineering, Whole Slide Images
Abstract: International audience; Quantifying the distribution and morphology of tau protein structures in brain tissues is key to diagnosing Alzheimer's Disease (AD) and its subtypes. Recently, deep learning (DL) models such as UNet have been successfully used for automatic segmentation of histopathological whole slide images (WSI) of biological tissues. In this study, we propose a DL-based methodology for semantic segmentation of tau lesions (i.e., neuritic plaques) in WSI of postmortem patients with AD. The state of the art in semantic segmentation of neuritic plaques in human WSI is very limited. Our study proposes a baseline able to generate a significant advantage for morphological analysis of these tauopathies for further stratification of AD patients. Essential discussions concerning biomarkers (ALZ50 versus AT8 tau antibodies), the imaging modality (different slide scanner resolutions), and the challenge of weak annotations are addressed within this seminal study. The analysis of the impact of context in plaque segmentation is important to understand the role of the micro-environment for reliable tau protein segmentation. In addition, by integrating visual interpretability, we are able to explain how the network focuses on a region of interest (ROI), giving additional insights to pathologists. Finally, the release of a new expert-annotated database and the code (https://github.com/aramis-lab/miccai2022-stratifiad.git) will be helpful for the scientific community to accelerate the development of new pipelines for human WSI processing in AD.
Published: 2022

4. Hydrophilic Fluorescent Nanoprodrug of Paclitaxel for Glioblastoma Chemotherapy

Author: Daniel, Jonathan, Montaleytang, Maeva, Nagarajan, Sounderya, Picard, Sébastien, Clermont, Guillaume, Lazar, Adina, Dumas, Noé, Correard, Florian, Braguer, Diane, Blanchard-Desce, Mireille, Esteve, Marie-Anne, Vaultier, Michel, Institut des Sciences Moléculaires (ISM), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Centre National de la Recherche Scientifique (CNRS), Institut des Sciences Chimiques de Rennes (ISCR), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes-Centre National de la Recherche Scientifique (CNRS), emlyon business school, Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Sorbonne Université (SU), Université Grenoble Alpes - UFR Pharmacie (UGA UFRP), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Synthèse et électrosynthèse organiques (SESO), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Hôpital de la Timone [CHU - APHM] (TIMONE), Institut National des Sciences Appliquées (INSA)-Université de Rennes (UNIV-RENNES)-Institut National des Sciences Appliquées (INSA)-Ecole Nationale Supérieure de Chimie de Rennes (ENSCR)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), ANR-10-IDEX-03-02, Agence Nationale de la Recherche, 2018-08, Institut National Du Cancer, Canceropôle PACA, PC201420, L?Institut Th?matique Multi-Organisme Cancer d'Aviesan, Université Grenoble Alpes - UFR Pharmacie [ ?-2019] (UGA UFRP [ ?-2019]), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1 (UB)-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Montesquieu - Bordeaux 4-Université Sciences et Technologies - Bordeaux 1-École Nationale Supérieure de Chimie et de Physique de Bordeaux (ENSCPB)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Blanchard-Desce, Mireille, and Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]
Subjects: Chemistry, [CHIM.THER] Chemical Sciences/Medicinal Chemistry, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, QD1-999, Article, ComputingMilieux_MISCELLANEOUS
Abstract: International audience; Highly water-soluble, nontoxic organic nano-particles on which paclitaxel (PTX), a hydrophobic anticancer drug, has been covalently bound via an ester linkage (4.5% of total weight) have been prepared for the treatment of glioblastoma. These soft fluorescent organic nanoparticles (FONPs), obtained from citric acid and diethylenetriamine by microwave-assisted condensation, show suitable size (Ø = 17− 30 nm), remarkable solubility in water, softness as well as strong blue fluorescence in an aqueous environment that are fully retained in cell culture medium. Moreover, these FONPs were demonstrated to show in vitro safety and preferential internalization in glioblastoma cells through caveolin/lipid raft-mediated endocytosis. The PTX-conjugated FONPs retain excellent solubility in water and remain stable in water (no leaching), while they showed anticancer activity against glioblastoma cells in two-dimensional and three-dimensional culture. PTX-specific effects on microtubules reveal that PTX is intracellularly released from the nanocarriers in its active form, in relation with an intracellular-promoted lysis of the ester linkage. As such, these hydrophilic prodrug formulations hold major promise as biocompatible nanotools for drug delivery.
Published: 2019

5. The Use of Localized Proteomics to Understand the Pathogenesis of Alzheimer's Disease

Author: Pires, Geoffrey V., Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université, New York University. School of Medicine, Marie-Claude Potier, Eleanor Drummond, and STAR, ABES
Subjects: Phosphorylates Tau, Tauopathies, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Maladie d’Alzheimer, Tau, Dégénérescences neurofibrillaires, Secernin-1, Protéomiques
Abstract: Alzheimer's disease (AD) is characterized by the extracellular aggregation of the Amyloid-ß peptide (Aß) in amyloid plaques and by the intraneuronal accumulation of aggregated hyperphosphorylated tau (pTau) in neurofibrillary tangles (NFTs). To date, our understanding of the molecular pathways and cellular circuits involved in the toxic effects of Aß and pTau is still incomplete. To better understand how pTau exerts its toxicity in AD, we used two complementary localized proteomics approaches: (i) a quantitative proteomics method performed on microdissected NFTs from AD patients, and (ii) an Affinity-Purification Mass Spectrometry method to identify NFT-associated proteins that specifically bind to pTau. In this study, we identified 542 proteins in NFTs, and confirmed that 75 proteins present in NFTs interacted with pTau. In addition, we also identified 13 novel interactors. Among these, SCRN1 was selected for further characterization. Immunohistochemistry showed that SCRN1 was a neuronal protein that abundantly accumulated in NFTs and plaque-associated dystrophic neurites throughout the progression of AD. Quantification of SCRN1 immunohistochemistry confirmed that SCRN1 preferentially accumulated in NFTs in comparison to surrounding non-tangle containing neurons, at both early and late stages of AD. Furthermore, this association between SCRN1 and pTau was unique to AD, and was not observed in other tauopathies. Thus, SCRN1 may be a novel therapeutic target and serve as a useful biomarker to distinguish AD from other tauopathies. In conclusion, we hope that proteomic studies such as ours will lead to a better understanding of the disease mechanisms occurring in AD and other tauopathies., La maladie d'Alzheimer (MA) se caractérise par l'agrégation extracellulaire du peptide Amyloid-ß (Aß) en plaques amyloïdes et par l'accumulation intraneuronale de Tau agrégée et anormalement phosphorylée (pTau) dans des dégénérescences neurofibrillaires (DNF). À ce jour, notre compréhension des voies moléculaires et circuits cellulaires issus des effets toxiques d'Aß et de pTau est encore incomplète. Afin de mieux comprendre comment pTau exerce sa toxicité dans la MA, nous avons utilisé deux approches complémentaires de protéomique localisée : (i) une méthode de protéomique quantitative réalisée sur des DNFs microdisséquées provenant de patients atteints de la MA, et (ii) une méthode d’Affinity-Purification Mass Spectrometry afin d’identifier les protéines associées aux DNFs qui se lient spécifiquement à pTau. Dans cette étude, nous avons identifié 542 protéines dans les DNFs, et confirmé que 75 protéines présentes dans les DNFs interagissaient avec la pTau. En outre, nous avons également identifié 13 nouveaux interacteurs. SCRN1 a été sélectionnée pour plus ample caractérisation. Nous avons montré que SCRN1 était une protéine neuronale qui s'accumulait dans les DNFs et les neurites dystrophiques associées aux plaques amyloïdes, et ceci tout à différents stades de la MA. La quantification de ces marquages a confirmé que SCRN1 s'accumulait préférentiellement dans les DNFs, aux stades précoce et avancé de la MA. En outre, cette association entre SCRN1 et la pTau était unique à la MA, et ne fut observée dans d'autres tauopathies. Ainsi, SCRN1 pourrait constituer une nouvelle cible thérapeutique et servir de biomarqueur utile pour la MA et autres tauopathies.
Published: 2021

6. TRIM9 and TRIM67 Are New Targets in Paraneoplastic Cerebellar Degeneration

Author: Sabine Brugière, Véronique Rogemond, Stephanie L. Gupton, Nicole Fabien, Joubert Bastien, Kunikazu Tanji, Jérôme Honnorat, Isabelle Quadrio, Le Duy Do, Virginie Desestret, Yohann Couté, Institut de Chimie et Biochimie Moléculaires et Supramoléculaires (ICBMS), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-École Supérieure de Chimie Physique Électronique de Lyon (CPE)-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), French Reference Center on Paraneoplastic Neurological Syndrome, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Lyon-Université de Lyon-Institut National des Sciences Appliquées de Lyon (INSA Lyon), Université de Lyon-Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Institut de Chimie du CNRS (INC)-École Supérieure Chimie Physique Électronique de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Centre de recherche en neurosciences de Lyon (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: Male, Pathology, Lung Neoplasms, Tripartite Motif Proteins, 0302 clinical medicine, Cerebrospinal fluid, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, Mice, Knockout, Neurons, 05 social sciences, Intracellular Signaling Peptides and Proteins, Brain, Paraneoplastic cerebellar degeneration, 3. Good health, Neurology, Encephalitis, Adenocarcinoma, Female, Cerebellar atrophy, medicine.symptom, medicine.medical_specialty, Ubiquitin-Protein Ligases, Nerve Tissue Proteins, Hashimoto Disease, Paraneoplastic Cerebellar Degeneration, Article, 050105 experimental psychology, 03 medical and health sciences, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Animals, Humans, 0501 psychology and cognitive sciences, Lung cancer, Aged, Autoantibodies, Autoimmune encephalitis, Cerebellar ataxia, business.industry, Cancer, medicine.disease, Small Cell Lung Carcinoma, Mice, Inbred C57BL, Cytoskeletal Proteins, Neurology (clinical), Carrier Proteins, business, Biomarkers, 030217 neurology & neurosurgery
Abstract: To describe autoantibodies (Abs) against tripartite motif-containing (TRIM) protein 9 and 67 in two patients with paraneoplastic cerebellar degeneration (PCD) associated with lung adenocarcinoma. Abs were characterized using immunohistochemistry, Western blotting, cultures of murine cortical, and hippocampal neurons, immunoprecipitation, mass spectrometry, knockout mice for Trim9 and 67, and cell-based assay. Control samples included sera from 63 patients with small cell lung cancer without any paraneoplastic neurological syndrome, 36 patients with lung adenocarcinoma and PNS, CSF from 100 patients with autoimmune encephalitis, and CSF from 165 patients with neurodegenerative diseases. We found Abs targeting TRIM9 and TRIM67 at high concentration in the serum and the cerebrospinal fluid (CSF) of a 78-year-old woman and a 65-year-old man. Both developed subacute severe cerebellar ataxia. Brain magnetic resonance imaging found no abnormality and no cerebellar atrophy. Both had CSF inflammation with mild pleiocytosis and a few oligoclonal bands. We identified a pulmonary adenocarcinoma, confirming the paraneoplastic neurological syndrome in both patients. They received immunomodulatory and cancer treatments without improvement of cerebellar ataxia, even though both were in remission of their cancer (for more than 10 years in one patient). Anti-TRIM9 and anti-TRIM67 Abs were specific to these two patients. All control serum and CSF samples tested were negative for anti-TRIM9 and 67. Anti-TRIM9 and anti-TRIM67 Abs appeared to be specific biomarkers of PCD and should be added to the panel of antigens tested when this is suspected.
Published: 2018

7. The Implementation of DNA Methylation Profiling into a Multistep Diagnostic Process in Pediatric Neuropathology: A 2-Year Real-World Experience by the French Neuropathology Network

Author: Melanie, Pages, Emmanuelle, Uro-Coste, Carole, Colin, David, Meyronet, Guillaume, Gauchotte, Claude-Alain, Maurage, Audrey, Rousseau, Catherine, Godfraind, Karima, Mokhtari, Karen, Silva, Dominique, Figarella-Branger, Pascale, Varlet, On Behalf Of The Renoclip-Loc Network, GHU Paris Psychiatrie et Neurosciences, Institut Universitaire du Cancer de Toulouse - Oncopole (IUCT Oncopole - UMR 1037), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de neurophysiopathologie (INP), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de Pathologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut de Pathologie [CHU Lille], Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de Recherche en Cancérologie et Immunologie Nantes-Angers (CRCINA), Université d'Angers (UA)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre hospitalier universitaire de Nantes (CHU Nantes), CHU Clermont-Ferrand, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital de la Timone [CHU - APHM] (TIMONE), HAL-SU, Gestionnaire, Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN)-Centre hospitalier universitaire de Nantes (CHU Nantes)-Centre National de la Recherche Scientifique (CNRS)-Université d'Angers (UA), and Laboratoire de Neuropathologie Raymond Escourolle
Subjects: 0301 basic medicine, Oncology, tumor classification, Cancer Research, medicine.medical_specialty, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.CAN]Life Sciences [q-bio]/Cancer, Neuropathology, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.CAN] Life Sciences [q-bio]/Cancer, molecular pathology, Internal medicine, medicine, Copy-number variation, Medical diagnosis, Grading (tumors), [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, DNA methylation, business.industry, Molecular pathology, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Methylation, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, 3. Good health, Dna methylation profiling, 030104 developmental biology, copy-number variation, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, pediatric CNS tumors, integrated diagnosis, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, 030217 neurology & neurosurgery
Abstract: Simple Summary Supported by the “easy-to-use” and free DKFZ central nervous system (CNS) tumor classification web tool, DNA methylation profiling is a method changing the routine diagnostic practice in neuro-oncology. This work depicts a real-world practice experience by the French neuropathology network of incorporating DNA methylation profiling into the diagnostic process of challenging pediatric CNS tumors. After two rounds of histopathological review by neuropathology experts—including morphology, neuroimaging, immunohistochemistry, panel sequencing and FISH—62 tumors still presenting diagnostic uncertainty were selected for DNA methylation profiling. Using the DKFZ “classifier” and combining all additional information obtained from DNA methylation array, we observed significant diagnostic refinements and amendments. DNA methylation was successful in a significant number of cases (71%) despite the complex specificities of the cohort. Our study evaluates how DNA methylation testing would impact diagnosis and presents illustrative and representative cases. Abstract DNA methylation profiling has recently emerged as a powerful tool to help establish diagnosis in neuro-oncology. Here we present our national diagnostic strategy as the French neuropathology network (RENOCLIP-LOC) and our current approach of integrating DNA methylation profiling into our multistep diagnostic process for challenging pediatric CNS tumors. The tumors with diagnostic uncertainty were prospectively selected for DNA methylation after two rounds of review by neuropathology experts. We first integrated the classifier score into the histopathological findings. Subsequent analyses using t-SNE (t-Distributed Stochastic Neighbor Embedding) representation were performed. An additional step consisted of analyzing copy-number variation data (CNV). Finally, we combined all data to establish diagnoses and evaluated the impact of DNA methylation profiling on diagnostic and grading changes that would affect patient management. Over two years, 62 pediatric tumors were profiled. (1) Integrating the classifier score to the histopathological findings impacted the diagnosis in 33 cases (53%). (2) t-SNE analysis provided arguments for diagnosis in 26/35 cases with calibrated scores
Published: 2021

8. CC17 group B Streptococcus exploits integrins for neonatal meningitis development

Author: Romain Deshayes de Cambronne, Lionel Costa, Caroline Rambaud, Martine Cohen-Salmon, Abdelouhab Bouaboud, Asmaa Tazi, Anne-Cécile Boulay, Anne-Sophie Bourrel, Agnès Fouet, Amandine Picart, Cristina Candeias, Claire Poyart, Julie Guignot, Guillaume Bouvier, Isabelle Plu, Cyril Anjou, Corinne Albiges-Rizo, Eva Faurobert, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Bioinformatique structurale - Structural Bioinformatics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Centre interdisciplinaire de recherche en biologie (CIRB), Labex MemoLife, École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Raymond Poincaré [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Centre national de Référence des Streptocoques (CNR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), This work was supported by Agence Nationale de la Recherche (ANR, grant StrepB2brain, ANR-17-CE15-0026-01). LC is a recipient of a postdoctoral fellowship from the ANR (StrepB2brain). ASB is a doctoral fellow funded by Université de Paris. RDDC was funded by FERCM., We are grateful to Pierre-Olivier Couraud (INSERM, Paris, France) for the gift of hCMEC/D3 cells, Alain Duperray for the gift of CHO-ICAM1 cells, Yoshikazu Takada for the gift of CHO-αvβ3 cells, and Glen Ulett for the gift of the GFP plasmid. We are extremely grateful to Nathalie Strazielle and Jean-François Ghersi-Egea from BIP (CRNL, Lyon, France) for choroid plexus isolation and helpful comments. We thank Matthieu Benard from the animal facility of the Institut Cochin and Marine Gaillard for their help with animal experiments and Thomas Guilbert and Fabienne Regnier for their help with brain slice clarification. We also thank the Imag’IC and HistIM core facilities of the Cochin Institute and Shaynoor Dramsi for anti-Srr1 antibody and for critical reading of the manuscript., ANR-17-CE15-0026,strepB2brain,Franchissement de la barrière hémato-méningée par le Streptocoque du groupe B hyper-virulent CC17(2017), Hôpitaux Universitaires Paris Centre (CHU Paris Centre), Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Collège de France (CdF (institution))-Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Fouet, Agnès, Franchissement de la barrière hémato-méningée par le Streptocoque du groupe B hyper-virulent CC17 - - strepB2brain2017 - ANR-17-CE15-0026 - AAPG2017 - VALID, Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-École normale supérieure - Paris (ENS-PSL), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: 0301 basic medicine, Group B Streptococcus, Integrins, [SDV]Life Sciences [q-bio], [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Clone (cell biology), medicine.disease_cause, Bacterial Adhesion, blood brain barrier (BBB), 0302 clinical medicine, Bacterial infections, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Internalization, reproductive and urinary physiology, media_common, Infectious disease, Streptococcus, meningitis, General Medicine, 3. Good health, Srr2, Blood-Brain Barrier, 030220 oncology & carcinogenesis, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Meningitis, Research Article, integrin, media_common.quotation_subject, Integrin, Biology, Microbiology, Neonatal meningitis, Cell Line, Meningitis, Bacterial, Streptococcus agalactiae, 03 medical and health sciences, [SDV.MHEP.PED] Life Sciences [q-bio]/Human health and pathology/Pediatrics, Streptococcal Infections, medicine, Animals, Humans, Receptors, Vitronectin, Adhesins, Bacterial, [SDV.MHEP.PED]Life Sciences [q-bio]/Human health and pathology/Pediatrics, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Integrin alphaVbeta3, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Rats, Bacterial adhesin, 030104 developmental biology, Animals, Newborn, biology.protein, neonatal susceptibility, bacteria, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, CC17
Abstract: We are grateful to Pierre-Olivier Couraud (INSERM, Paris, France) for the gift of hCMEC/D3 cells, Alain Duperray for the gift of CHO-ICAM1 cells, Yoshikazu Takada for the gift of CHO-αvβ3 cells, and Glen Ulett for the gift of the GFP plasmid. We are extremely grateful to Nathalie Strazielle and Jean-François Ghersi-Egea from BIP (CRNL, Lyon, France) for choroid plexus isolation and helpful comments. We thank Matthieu Benard from the animal facility of the Institut Cochin and Marine Gaillard for their help with animal experiments and Thomas Guilbert and Fabienne Regnier for their help with brain slice clarification. We also thank the Imag’IC and HistIM core facilities of the Cochin Institute and Shaynoor Dramsi for anti-Srr1 antibody and for critical reading of the manuscript.; International audience; Group B Streptococcus (GBS) is the major cause of human neonatal infections. A single clone, designated CC17-GBS, accounts for more than 80% of meningitis cases, the most severe form of the infection. However, the events allowing blood-borne GBS to penetrate the brain remain largely elusive. In this study, we identified the host transmembrane receptors α5β1 and αvβ3 integrins as the ligands of Srr2, a major CC17-GBS-specific adhesin. Two motifs located in the binding region of Srr2 were responsible for the interaction between CC17-GBS and these integrins. We demonstrated in a blood-brain-barrier cellular model that both integrins contributed to the adhesion and internalization of CC17-GBS. Strikingly, both integrins were overexpressed during the postnatal period in the brain vessels of the blood-brain barrier and blood-cerebrospinal fluid barrier and contributed to juvenile susceptibility to CC17 meningitis. Finally, blocking these integrins decreased the ability of CC17-GBS to cross into the CNS of juvenile mice in an in vivo model of meningitis. Our study demonstrated that CC17-GBS exploits integrins in order to cross the brain vessels, leading to meningitis. Importantly, it provides host molecular insights into neonate's susceptibility to CC17-GBS meningitis, thereby opening new perspectives for therapeutic and prevention strategies of GBS-elicited meningitis.
Published: 2021

9. Pathway from TDP-43-Related Pathology to Neuronal Dysfunction in Amyotrophic Lateral Sclerosis and Frontotemporal Lobar Degeneration

Author: Shinsuke Ishigaki, Yohei Iguchi, Susana Boluda, Charles Duyckaerts, Mari Yoshida, Yuichi Riku, Danielle Seilhean, Masahisa Katsuno, Yasushi Iwasaki, Gen Sobue, Gestionnaire, Hal Sorbonne Université, Nagoya University, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Pathology, Cytoplasmic inclusion, TDP-43, [SDV]Life Sciences [q-bio], Review, Synapse, lcsh:Chemistry, Transactivation, 0302 clinical medicine, Loss of Function Mutation, synapse, Nuclear protein, Amyotrophic lateral sclerosis, lcsh:QH301-705.5, Spectroscopy, Neurons, 0303 health sciences, General Medicine, Frontotemporal lobar degeneration, Immunohistochemistry, Computer Science Applications, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Gain of Function Mutation, Disease Susceptibility, FTLD, Protein Binding, Signal Transduction, medicine.medical_specialty, autophagy, tau Proteins, Biology, Protein Aggregation, Pathological, Catalysis, Exocytosis, Inorganic Chemistry, 03 medical and health sciences, mental disorders, medicine, Humans, Physical and Theoretical Chemistry, Molecular Biology, 030304 developmental biology, Organic Chemistry, Autophagy, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, medicine.disease, nervous system diseases, lcsh:Biology (General), lcsh:QD1-999, Frontotemporal Lobar Degeneration, ALS, 030217 neurology & neurosurgery, Biomarkers
Abstract: International audience; Transactivation response DNA binding protein 43 kDa (TDP-43) is known to be a pathologic protein in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). TDP-43 is normally a nuclear protein, but affected neurons of ALS or FTLD patients exhibit mislocalization of nuclear TDP-43 and cytoplasmic inclusions. Basic studies have suggested gain-of-neurotoxicity of aggregated TDP-43 or loss-of-function of intrinsic, nuclear TDP-43. It has also been hypothesized that the aggregated TDP-43 functions as a propagation seed of TDP-43 pathology. However, a mechanistic discrepancy between the TDP-43 pathology and neuronal dysfunctions remains. This article aims to review the observations of TDP-43 pathology in autopsied ALS and FTLD patients and address pathways of neuronal dysfunction related to the neuropathological findings, focusing on impaired clearance of TDP-43 and synaptic alterations in TDP-43-related ALS and FTLD. The former may be relevant to intraneuronal aggregation of TDP-43 and exocytosis of propagation seeds, whereas the latter may be related to neuronal dysfunction induced by TDP-43 pathology. Successful strategies of disease-modifying therapy might arise from further investigation of these subcellular alterations. View Full-Text
Published: 2021

10. Propagation axonale des pathologies Tau et Aβ dans la maladie d'Alzheimer : à la recherche de propagons dans le circuit subiculo-fornico-mamillaire

Author: Thierry, Manon, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université, Charles Duyckaerts, Marie-Claude Potier, and STAR, ABES
Subjects: [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Alzheimer's disease, Maladie d’Alzheimer, Subiculo-fornico-mamillary system, Axons, Système subiculo-fornico-mamillaire, nervous system, Propagons, mental disorders, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Tau, Axones, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Aβ
Abstract: In Alzheimer's disease, accumulations of Tau and Aβ involve successively discontinuous but connected regions. The role of axons in this progression was studied in an isolated bundle of axons connecting the subiculum to the mamillary body: the pillar of the fornix (PF). A histological analysis of 47 post-mortem cases of various severities was performed. The subiculum was affected before the mamillary body. Only accumulations of Tau – not of Aβ – were detected in the PF. Axonal Tau accumulations were abnormally phosphorylated (AT8 and TG3 positive) but non-fibrillary (Gallyas negative). They induced the aggregation of Tau P301S in cell biosensors as prions – or "propagons". Accumulations of Tau or Aβ could both appear first in this system; the severities of Tau pathology in the PF and of Aβ accumulation in the mamillary body were yet correlated. Aβ deposits were seen in contact with Tau positive axons in the mamillary body where the PF ends, after CLARITY and microcryodissection. The axons of the PF transport non-fibrillary Tau propagons, transmitting the pathology from the subiculum to the mamillary body. The absence of hierarchy between Tau and Aβ pathologies in this system is incompatible with a cause and effect relationship. Both pathologies were, however, correlated and intimately associated, indicating an interaction of the two processes once initiated., Dans la maladie d’Alzheimer, les accumulations de Tau et d’Aβ apparaissent successivement dans des régions discontinues mais connectées. Le rôle des axones dans cette progression lésionnelle a été étudié dans le pilier du fornix (PF), un faisceau axonal isolé reliant le subiculum au corps mamillaire. Une analyse histologique de 47 cas post-mortem de sévérités variées a été réalisée. Le subiculum était affecté avant le corps mamillaire. Seules des accumulations de Tau – et non d'Aβ – ont été détectées dans le PF ; elles étaient anormalement phosphorylées (AT8 et TG3 positives) mais non fibrillaires (Gallyas négatives). Ces accumulations induisaient l’agrégation de Tau P301S dans des biosenseurs cellulaires telles des prions, ou « propagons ». Les accumulations de Tau ou d’Aβ pouvaient être chacune initiales dans ce système. Les pathologies Tau du PF et Aβ du corps mamillaire étaient cependant corrélées. Des dépôts d’Aβ au contact d’axones Tau positifs ont été vus dans le corps mamillaire près de l’arrivée du PF, par CLARITY et par microcryodissection. Le PF transporte des propagons Tau non fibrillaires, transmettant la pathologie du subiculum au corps mamillaire. Aucun ordre hiérarchique constant n’a été établi entre les pathologies Tau et Aβ. Les deux pathologies sont néanmoins corrélées et associées, indiquant une synergie de ces processus, indépendamment initiés.
Published: 2020

11. Identification of Umbre Orthobunyavirus as a Novel Zoonotic Virus Responsible for Lethal Encephalitis in 2 French Patients with Hypogammaglobulinemia

Author: Franck Bielle, Sophie Demeret, David Brassat, Philippe Pérot, Susana Boluda, Fabrice Bonneville, Charles Duyckaerts, Anne Huard de Verneuil, Grégory L'Ambert, Bertrand Mathon, Marie Bernadette Delisle, Delphine Chrétien, Jan Hellert, Karine Bollore, Vincent Foulongne, Isabelle Plu, Karima Mokhtari, Muriel Coulpier, Claire Fieschi, Patricia Gil, Edouard de Sousa Cunha, Thérèse Couderc, Marc Eloit, Marion Malphettes, Marie Flamand, Serafin Gutierrez, Carole Tamietti, Thomas Bigot, Danielle Seilhean, Sarah Temmam, Découverte de pathogènes – Pathogen discovery, Institut Pasteur [Paris] (IP), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Etablissement français du don du sang [Montpellier], Pathogenesis and Control of Chronic and Emerging Infections (PCCEI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université des Antilles (UA)-Etablissement français du don du sang [Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), Entente Interdépartementale pour la démoustication du littoral méditerranéen (EID), Virologie Structurale - Structural Virology, Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Normandie, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre national de référence des Agents Transmissibles Non Conventionnels, Institut de Veille Sanitaire (INVS), Santé publique France - French National Public Health Agency [Saint-Maurice, France], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Toulouse Neuro Imaging Center (ToNIC), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Université Toulouse - Jean Jaurès (UT2J)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées, Centre de Physiopathologie Toulouse Purpan (CPTP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Pôle Neurosciences [CHU Toulouse], Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Université Paris Diderot - Paris 7 (UPD7)-Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), CHU Charles Foix [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre d'investigation clinique Neurosciences [CHU Pitié Salpêtrière] (CIC Neurosciences), Centre d'investigation clinique pluridisciplinaire [CHU Pitié Salpêtrière] (CIC-P 1421), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], École nationale vétérinaire - Alfort (ENVA), This work was supported by the Laboratoire d’Excellence 'Integrative Biology of Emerging Infectious Diseases' (grant number ANR-10-LABX-62-IBEID)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Pérot, Philippe, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Institut Pasteur [Paris], Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Université des Antilles (UA)-Etablissement français du don du sang [Montpellier]-Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], École nationale vétérinaire d'Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), CHU Toulouse [Toulouse], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Hôpital Purpan [Toulouse], CHU Toulouse [Toulouse]-CHU Toulouse [Toulouse], Pôle neurosciences [Hôpital de Purpan - Toulouse], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), École nationale vétérinaire d'Alfort (ENVA), École nationale vétérinaire - Alfort (ENVA)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Toulouse Mind & Brain Institut (TMBI), Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université Toulouse - Jean Jaurès (UT2J), Université de Toulouse (UT)-Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT), and Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Microbiology (medical), [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Orthobunyavirus, Culex, viruses, [SDE.MCG]Environmental Sciences/Global Changes, Population, Arbovirus, Virus, Serology, 03 medical and health sciences, 0302 clinical medicine, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Agammaglobulinemia, Umbre virus, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Culex pipiens, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Animals, Humans, education, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, metatranscriptomics, biology, business.industry, biology.organism_classification, medicine.disease, Virology, 3. Good health, Europe, [SDE.MCG] Environmental Sciences/Global Changes, 030104 developmental biology, Infectious Diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viruses, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Encephalitis, next-generation sequencing, France, business, 030217 neurology & neurosurgery
Abstract: Background Human encephalitis represents a medical challenge from a diagnostic and therapeutic point of view. We investigated the cause of 2 fatal cases of encephalitis of unknown origin in immunocompromised patients. Methods Untargeted metatranscriptomics was applied on the brain tissue of 2 patients to search for pathogens (viruses, bacteria, fungi, or protozoans) without a prior hypothesis. Results Umbre arbovirus, an orthobunyavirus never previously identified in humans, was found in 2 patients. In situ hybridization and reverse transcriptase–quantitative polymerase chain reaction (RT-qPCR) showed that Umbre virus infected neurons and replicated at high titers. The virus was not detected in cerebrospinal fluid by RT-qPCR. Viral sequences related to Koongol virus, another orthobunyavirus close to Umbre virus, were found in Culex pipiens mosquitoes captured in the south of France where the patients had spent some time before the onset of symptoms, demonstrating the presence of the same clade of arboviruses in Europe and their potential public health impact. A serological survey conducted in the same area did not identify individuals positive for Umbre virus. The absence of seropositivity in the population may not reflect the actual risk of disease transmission in immunocompromised individuals. Conclusions Umbre arbovirus can cause encephalitis in immunocompromised humans and is present in Europe.
Published: 2020

12. Immunopathological characterization of ovarian teratomas associated with anti-N-methyl-D-aspartate receptor encephalitis

Author: Chefdeville, Aude, Treilleux, Isabelle, Mayeur, Marie-Eve, Couillault, Coline, Picard, Géraldine, Bost, Chloé, Mokhtari, Karima, Vasiljevic, Alexandre, Meyronet, David, Rogemond, Véronique, Psimaras, Dimitri, Dubois, Bertrand, Honnorat, Jérôme, Desestret, Virginie, Institut NeuroMyoGène (INMG), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université de Lyon, Centre Léon Bérard [Lyon], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Centre de Référence Maladie Rare 'Syndromes neurologiques Paranéoplasiques', Hospices Civils de Lyon (HCL)-Hopital Neurologique, Hospices Civils de Lyon (HCL), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Gestionnaire, Hal Sorbonne Université
Subjects: Anti-N-Methyl-D-Aspartate Receptor Encephalitis, Ovarian Neoplasms, B-Lymphocytes, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], endocrine system, endocrine system diseases, Research, T-Lymphocytes, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Teratoma, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Brain, Ovarian teratoma, Autoimmunity, lcsh:RC346-429, female genital diseases and pregnancy complications, nervous system, Anti-NMDAR encephalitis, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, Female, Neoplasm Grading, neoplasms, lcsh:Neurology. Diseases of the nervous system
Abstract: Encephalitis with anti-NMDAR antibodies (NMDAR-E) is a severe autoimmune neurological disorder, defined by a clinical presentation of encephalitis and the presence of IgG targeting the GluN1 subunit of NMDA receptors in the CSF. An underlying ovarian teratoma is commonly associated with this autoimmune disease suggesting a role of the tumor in immunopathogenesis. In this study, we characterized the salient histopathological features of 27 ovarian teratomas associated with NMDAR-E (3 immature and 24 mature teratomas) and 40 controls without associated encephalitis. All but one NMDAR-E-associated teratomas contained a nervous tissue component, while less than 40% of control teratomas did (p
Published: 2019

13. Interrupted CAG expansions in ATXN2 gene expand the genetic spectrum of frontotemporal dementias

Author: Clémence Fournier, Vincent Anquetil, Agnès Camuzat, Sandrine Stirati-Buron, Véronique Sazdovitch, Laura Molina-Porcel, Sabrina Turbant, Daisy Rinaldi, Raquel Sánchez-Valle, Mathieu Barbier, Morwena Latouche, Neuro-CEB Neuropathology Network, Giovanni Stevanin, Danielle Seilhean, Alexis Brice, Charles Duyckaerts, Isabelle Le Ber, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neurologie et thérapeutique expérimentale, Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR70-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Imagerie Moléculaire et Stratégies Théranostiques (IMoST), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Clermont Auvergne [2017-2020] (UCA [2017-2020]), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR70-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Université Clermont Auvergne [2017-2020] (UCA [2017-2020])-Institut National de la Santé et de la Recherche Médicale (INSERM)
Subjects: Male, TDP-43, Ataxin 2, [SDV.CAN]Life Sciences [q-bio]/Cancer, Frontotemporal lobar degeneration, lcsh:RC346-429, Cohort Studies, SCA2, C9orf72, Humans, Letter to the Editor, lcsh:Neurology. Diseases of the nervous system, ComputingMilieux_MISCELLANEOUS, Aged, Ataxin-2, Aged, 80 and over, Tomography, Emission-Computed, Single-Photon, Corticobasal degeneration, Brain, Middle Aged, Amyotrophic lateral sclerosis, Corticobasal syndrome, Magnetic Resonance Imaging, DNA-Binding Proteins, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, Trinucleotide Repeat Expansion, Frontotemporal dementia, GRN
Abstract: Letter to the Editor - no abstract available
Published: 2018

14. Integrated multi-omics analysis of oligodendroglial tumours identifies three subgroups of 1p/19q co-deleted gliomas

Author: Anne Jouvet, Karima Mokhtari, Marc Sanson, Eric Letouzé, François Ducray, Ahmed Idbaih, Aurélien de Reyniès, Nadine Martin-Duverneuil, Emmanuelle Uro-Coste, Caroline Dehais, Aurélie Kamoun, Dominique Figarella-Branger, Catherine Carpentier, Carole Colin, Jean-Yves Delattre, Nabila Elarouci, (le programme) Cartes d'identité des tumeurs (CIT), Ligue Nationales Contre le Cancer (LNCC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), OncoNeuroTek [Paris], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), and HAL UPMC, Gestionnaire
Subjects: Male, 0301 basic medicine, General Physics and Astronomy, Transcriptome, Cluster Analysis, Aged, 80 and over, Neurons, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Multidisciplinary, Stem Cells, Genomics, Glioma, Middle Aged, 3. Good health, Oligodendroglia, medicine.anatomical_structure, Chromosomes, Human, Pair 1, DNA methylation, Female, Chromosome Deletion, Signal Transduction, Adult, Cell type, Science, Oligodendroglioma, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Proto-Oncogene Proteins c-myc, Young Adult, 03 medical and health sciences, medicine, Humans, Survival analysis, Aged, Gene Expression Profiling, General Chemistry, DNA Methylation, medicine.disease, Survival Analysis, Oligodendrocyte, Gene expression profiling, 030104 developmental biology, Cancer research, Chromosomes, Human, Pair 19, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Oligodendroglial tumours (OT) are a heterogeneous group of gliomas. Three molecular subgroups are currently distinguished on the basis of the IDH mutation and 1p/19q co-deletion. Here we present an integrated analysis of the transcriptome, genome and methylome of 156 OT. Not only does our multi-omics classification match the current classification but also reveals three subgroups within 1p/19q co-deleted tumours, associated with specific expression patterns of nervous system cell types: oligodendrocyte, oligodendrocyte precursor cell (OPC) and neuronal lineage. We confirm the validity of these three subgroups using public datasets. Importantly, the OPC-like group is associated with more aggressive clinical and molecular patterns, including MYC activation. We show that the MYC activation occurs through various alterations, including MYC genomic gain, MAX genomic loss, MYC hypomethylation and microRNA-34b/c down-regulation. In the lower grade glioma TCGA dataset, the OPC-like group is associated with a poorer outcome independently of histological grade. Our study reveals previously unrecognized heterogeneity among 1p/19q co-deleted tumours., Oligodendroglial tumours are characterized into three different molecular subtypes. Here, the authors use genomic data to identify a further three subgroups of 1p/19q co-deleted tumours and demonstrate an association with an aggressive phenotype.
Published: 2016

15. Frontotemporal lobar degenerations, RNAopathy leading to proteinopathies

Author: Anquetil, Vincent, Bertrand, Anne, Camuzat, Agnès, Grange, Pierre de La, Fournier, Clémence, Buée-Scherrer, Valérie, Deramecourt, Vincent, Sergeant, Nicolas, Barbier, Mathieu, Buée, Luc, Brice, Alexis, Duyckaerts, Charles, Le Ber, Isabelle, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Infections Parasitaires : Transmission, Physiopathologie et Thérapeutiques (IP-TPT), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Service de Santé des Armées, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neuroradiologie diagnostique et fonctionnelle [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Service de Santé des Armées-Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: ComputingMilieux_MISCELLANEOUS, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience
Published: 2017

16. Characteristics in limbic encephalitis with anti–adenylate kinase 5 autoantibodies

Author: Sabine Brugière, Christine Lebrun-Frenay, Eve Chanson, Bastien Joubert, Véronique Rogemond, Le-Duy Do, Thomas de Brouker, François Ducray, Maïté Formaglio, François Tison, Jonathan Curot, Virginie Desestret, Yohann Couté, Jean-Yves Delattre, J. Honnorat, Catherine Thomas-Antérion, Laura Borrega, Jean-Christophe Antoine, Brice Laurens, Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Etude de la dynamique des protéomes (EDyP ), Laboratoire de Biologie à Grande Échelle (BGE - UMR S1038), Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Service de Neurologie [Lyon], CHU Lyon, French Reference Center on Paraneoplastic Neurological Syndrome, Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Service de neurologie, Hôpital Bellevue, Université de Bordeaux (UB), Service de neurologie [Bordeaux], CHU Bordeaux [Bordeaux]-Groupe hospitalier Pellegrin, CHU Toulouse [Toulouse], Department of Neurology, Centre Hospitalier Universitaire de Nice (CHU Nice), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne (CHU de Saint-Etienne), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019])-Institut de Recherche Interdisciplinaire de Grenoble (IRIG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de Neurologie [CHU de Saint-Étienne], Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E)-Université Jean Monnet - Saint-Étienne (UJM), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and Centre Sclérose Latérale Amyotrophique et maladies du motoneurone [CHU Saint-Etienne]
Subjects: Male, 0301 basic medicine, Pathology, medicine.medical_specialty, Anterograde amnesia, [SDV]Life Sciences [q-bio], Tau protein, Hippocampal formation, Diagnosis, Differential, 03 medical and health sciences, 0302 clinical medicine, Limbic Encephalitis, medicine, Humans, Cognitive decline, ComputingMilieux_MISCELLANEOUS, Aged, Autoantibodies, Retrospective Studies, Aged, 80 and over, Neurons, biology, business.industry, Adenylate Kinase, Limbic encephalitis, Autoantibody, Brain, Middle Aged, medicine.disease, 3. Good health, HEK293 Cells, Treatment Outcome, 030104 developmental biology, biology.protein, Immunohistochemistry, Female, Immunotherapy, Neurology (clinical), medicine.symptom, Antibody, business, Biomarkers, 030217 neurology & neurosurgery
Abstract: Objective:To report 10 patients with limbic encephalitis (LE) and adenylate kinase 5 autoantibodies (AK5-Abs).Methods:We conducted a retrospective study in a cohort of 50 patients with LE with uncharacterized autoantibodies and identified a specific target using immunohistochemistry, Western blotting, immunoprecipitation, mass spectrometry, and cell-based assay.Results:AK5 (a known autoantigen of LE) was identified as the target of antibodies in the CSFs and sera of 10 patients with LE (median age 64 years; range 57–80), which was characterized by subacute anterograde amnesia without seizure and sometimes preceded by a prodromal phase of asthenia or mood disturbances. Anterograde amnesia can be isolated, but some patients also complained of prosopagnosia, paroxysmal anxiety, or abnormal behavior. No associated cancer was observed. All 10 patients had bilateral hippocampal hypersignal on a brain MRI. CSF analysis generally showed a mild pleiocytosis with elevated immunoglobulin G index and oligoclonal bands, as well as high levels of tau protein with normal concentration of Aβ42 and phospho-tau, suggesting a process of neuronal death. Except for one patient, clinical response to immunotherapy was unfavorable, with persistence of severe anterograde amnesia. Two patients evolved to severe cognitive decline. Hippocampal atrophy was observed on control brain MRI. Using in vitro tests on hippocampal neurons, we did not identify clues suggesting a direct pathogenic role of AK5-Abs.Conclusions:AK5-Abs should be systematically considered in aged patients with subacute anterograde amnesia. Recognition of this disorder is important to develop new treatment strategies to prevent irreversible limbic damage.
Published: 2017

17. Accuracy of diagnosis criteria in patients with suspected diagnosis of sporadic Creutzfeldt-Jakob disease and detection of 14-3-3 protein, France, 1992 to 2009

Author: N. Delasnerie-Laupretre, Stéphane Haïk, Véronique Sazdovitch, Danielle Seilhean, Jean-Jacques Hauw, Charles Duyckaerts, Laurène Peckeu, Jean-Louis Laplanche, Jean-Philippe Brandel, D. Salomon, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Cellule Natl Reference Malad Creutzfeldt Jakob, Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP - HP), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service de Biochimie [AP-HP Hôpitaux Saint-Louis Lariboisière], Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Service de Neuropathologie Raymond Escourolle [CHU Pitié Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Académie nationale de médecine, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Hôpital Universitaire Pitié Salpêtrière, Assistance Publique - Hôpitaux de Paris ( AP - HP ), Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité ( CRESS (U1153 / UMR_A 1125) ), Université Sorbonne Paris Cité ( USPC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Recherche Agronomique ( INRA ), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC ), Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Neuropathologie [CHU Pitié Salpêtrière], HAL UPMC, Gestionnaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: 0301 basic medicine, Pathology, Epidemiology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autopsy, Disease, Electroencephalography, Surveillance and Outbreak Report, Creutzfeldt-Jakob Syndrome, 0302 clinical medicine, Cerebrospinal fluid, medicine.diagnostic_test, Brain, [ SDV.SPEE ] Life Sciences [q-bio]/Santé publique et épidémiologie, Magnetic Resonance Imaging, 3. Good health, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, surveillance, Female, France, medicine.medical_specialty, Prions, Sensitivity and Specificity, Prion Proteins, prion, 03 medical and health sciences, Nervous system disease, Virology, mental disorders, medicine, Humans, 14-3-3 protein, business.industry, Public Health, Environmental and Occupational Health, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, biomarkers, Magnetic resonance imaging, medicine.disease, Creutzfeldt-Jakob disease, nervous system diseases, 030104 developmental biology, 14-3-3 Proteins, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, diagnosis criteria, business, 030217 neurology & neurosurgery
Abstract: International audience; Diagnostic criteria of Creutzfeldt–Jakob disease (CJD), a rare and fatal transmissible nervous system disease with public health implications, are determined by clinical data, electroencephalogram (EEG), detection of 14-3-3 protein in cerebrospinal fluid (CSF), brain magnetic resonance imaging and prion protein gene examination. The specificity of protein 14-3-3 has been questioned. We reviewed data from 1,572 autopsied patients collected over an 18-year period (1992–2009) and assessed whether and how 14-3-3 detection impacted the diagnosis of sporadic CJD in France, and whether this led to the misdiagnosis of treatable disorders. 14-3-3 detection was introduced into diagnostic criteria for CJD in 1998. Diagnostic accuracy decreased from 92% for the 1992–1997 period to 85% for the 1998–2009 period. This was associated with positive detections of 14-3-3 in cases with negative EEG and alternative diagnosis at autopsy. Potentially treatable diseases were found in 163 patients (10.5%). This study confirms the usefulness of the recent modification of diagnosis criteria by the addition of the results of CSF real-time quaking-induced conversion, a method based on prion seed-induced misfolding and aggregation of recombinant prion protein substrate that has proven to be a highly specific test for diagnosis of sporadic CJD.
Published: 2017

18. Ceramides and sphingomyelinases in senile plaques

Author: Luce Dauphinot, Maï Panchal, Olivier Laprévote, Massimo Masserini, Isabelle Rivals, Charles Duyckaerts, Adina N. Lazar, Delphine Dargère, Nicolas Auzeil, Sophie Ayciriex, Elisa Salvati, Mathieu Gaudin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Géosciences Marines (GM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Neurobiologie, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Panchal, M, Gaudin, M, Lazar, A, Salvati, E, Rivals, I, Ayciriex, S, Dauphinot, L, Dargère, D, Auzeil, N, Masserini, M, Laprévote, O, Duyckaerts, C, Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), ICNS - Institut de Chimie des Substances naturelles, Unité de recherche Géosciences Marines (Ifremer) ( GM ), Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), Equipe de Statistique Appliquée ( ESA ), ESPCI ParisTech, ESPCI ParisTech-Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Unité de recherche Géosciences Marines (Ifremer) (GM), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre National de la Recherche Scientifique (CNRS)-Université de Lyon-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-École normale supérieure - Lyon (ENS Lyon), Equipe de Statistique Appliquée (ESA), ESPCI ParisTech-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP]
Subjects: Male, Amyloid beta-Peptide, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Plaque, Amyloid, Ceramide, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], 0302 clinical medicine, Senile plaques, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, Aged, 80 and over, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Chemistry, Lipid, Middle Aged, Lipidome, BIO/10 - BIOCHIMICA, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Sphingomyelin Phosphodiesterase, medicine.anatomical_structure, Neurology, Biochemistry, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, Alzheimer's disease, Alzheimer disease, Sphingomyelin, Microdissection, Human, Electrospray ionization, Fibril, Ceramides, lcsh:RC321-571, 03 medical and health sciences, Apolipoproteins E, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Aβ peptide, Lipidomics, Neuropil, medicine, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, Aged, 030304 developmental biology, Amyloid beta-Peptides, Senile plaque, Mass spectrometry, Lipidomic, Surface Plasmon Resonance, medicine.disease, Molecular biology, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Sphingomyelinase, Laser microdissection, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Chromatography, Liquid
Abstract: The senile plaque is a hallmark lesion of Alzheimer disease (AD). We compared, without a priori, the lipidome of the senile plaques and of the adjacent plaque-free neuropil. The analysis by liquid chromatography coupled with electrospray ionization mass spectrometry revealed that laser microdissected senile plaques were enriched in saturated ceramides Cer(d18:1/18:0) and Cer(d18:1/20:0) by 33 and 78% respectively with respect to the surrounding neuropil. This accumulation of ceramides was not explained by their affinity for Aβ deposits: no interaction between ceramide-liposomes and Aβ fibrils was observed in vitro by surface plasmon resonance and fluorescent ceramide-liposomes showed no affinity for the senile plaques in AD brain tissue. Accumulation of ceramides could be, at least partially, the result of a local production by acid and neutral sphingomyelinases that we found to be present in the corona of the senile plaques. © 2014 Elsevier Inc.
Published: 2014

19. The transcription coactivator ASC-1 is a regulator of skeletal myogenesis, and its deficiency causes a novel form of congenital muscle disease

Author: Brigitte Buendia, Alain Lilienbaum, Ana Ferreiro, Julien Fauré, Corinne Dill, C. Julien, Eva Cabet, Agnès Guichet, John Rendu, C. Chauveau, Pascale Marcorelles, Nathalie Vadrot, Marie Christine Minot, Odile Dubourg, Isabelle Duband-Goulet, L. Lazaro, Jean Paul Leroy, Laurianne Davignon, Valérie Allamand, Sylvie Odent, Groupe Myologie, Institut de Myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), INSERM U836, équipe 4, Muscles et pathologies, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Laboratoire de biochimie et génétique moléculaire, CHU Grenoble, CHU Pontchaillou [Rennes], Centre de recherche en myologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Service de génétique clinique [Rennes], Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud, Service de pédiatrie, Centre Hospitalier de la Côte Basque (CHCB), Anatomopathologie Pathologique, CHRU Hôpital Morvan, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de Pédiatrie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Raymond Poincaré [AP-HP]-Centre de Référence Maladies Neuromusculaires (GNMH), the Association Institut de Myologie, the Institut National de la Santé et la Recherche Médicale (Inserm), the Université Pierre et Marie Curie and the Université Paris Diderot, France, the International Graduate Program for Muscle Sciences, GK1631 ‘Myograd’, Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Joseph Fourier - Grenoble 1 (UJF), Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Le CHCB, Centre Hospitalier de la Côte Basque, Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Association française contre les myopathies (AFM-Téléthon)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Grenoble-Université Joseph Fourier - Grenoble 1 (UJF), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Association française contre les myopathies (AFM-Téléthon)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-Hôpital Sud, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], CHU Pitié-Salpêtrière [APHP], and Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-AP-HP Hôpital Raymond Poincaré [Garches]-Centre de Référence Maladies Neuromusculaires (GNMH)
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, Pathology, Adolescent, RNA Stability, Cellular differentiation, [SDV]Life Sciences [q-bio], Nonsense mutation, Biology, Muscle Development, Cell Line, Mice, 03 medical and health sciences, 0302 clinical medicine, Muscular Diseases, Internal medicine, Genetics, medicine, Animals, Humans, Myocyte, Genetic Predisposition to Disease, Child, Muscle, Skeletal, Myopathy, Molecular Biology, Genetics (clinical), Muscle contracture, Myogenesis, Gene Expression Regulation, Developmental, Infant, Muscle weakness, Skeletal muscle, Cell Differentiation, Sequence Analysis, DNA, General Medicine, Pedigree, 030104 developmental biology, Endocrinology, medicine.anatomical_structure, Codon, Nonsense, Female, medicine.symptom, 030217 neurology & neurosurgery, Genome-Wide Association Study, Transcription Factors
Abstract: International audience; Despite recent progress in the genetic characterization of congenital muscle diseases, the genes responsible for a significant proportion of cases remain unknown. We analysed two branches of a large consanguineous family in which four patients presented with a severe new phenotype, clinically marked by neonatal-onset muscle weakness predominantly involving axial muscles, life-threatening respiratory failure, skin abnormalities and joint hyperlaxity without contractures. Muscle biopsies showed the unreported association of multi-minicores, caps and dystrophic lesions. Genome-wide linkage analysis followed by gene and exome sequencing in patients identified a homozygous nonsense mutation inTRIP4encoding Activating Signal Cointegrator-1 (ASC-1), a poorly characterized transcription coactivator never associated with muscle or with human inherited disease. This mutation resulted inTRIP4mRNA decay to around 10% of control levels and absence of detectable protein in patient cells. ASC-1 levels were higher in axial than in limb muscles in mouse, and increased during differentiation in C2C12 myogenic cells. Depletion of ASC-1 in cultured muscle cells from a patient and inTrip4knocked-down C2C12 led to a significant reduction in myotube diameterex vivoandin vitro, without changes in fusion index or markers of initial myogenic differentiation. This work reports the firstTRIP4mutation and defines a novel form of congenital muscle disease, expanding their histological, clinical and molecular spectrum. We establish the importance of ASC-1 in human skeletal muscle, identify transcriptional co-regulation as novel pathophysiological pathway, define ASC-1 as a regulator of late myogenic differentiation and suggest defects in myotube growth as a novel myopathic mechanism
Published: 2016

20. ADAM30 Downregulates APP-Linked Defects Through Cathepsin D Activation in Alzheimer's Disease

Author: Pierre Dourlen, Yves Lemoine, Amandine Flaig, Frédéric Checler, Anne Marie Ayral, Jean-Charles Lambert, Kris Gevaert, Mathias Laga, Fanny Eysert, Tiago Mendes, David M. A. Mann, Linda Chami, Anne Sophie Hérard, Thierry Delzescaux, Franck Lafont, Florie Demiautte, Franck Hansmannel, Benoit Deprez, Charlotte Delay, David Hot, Florence Leroux, Bart Dermaut, Philippe Amouyel, Ludovic Huot, Yoann Sottejeau, Florence Pasquier, Nicolas Souedet, Florent Letronne, Charlotte Bauer, Marc Dhenain, Marie Lesaffre, Geoffroy Laumet, Nicolas Malmanche, David Tulasne, Claudine Berr, Rebecca Deprez, Julie Dumont, Elisabeth Werkmeister, Michel E. Vandenberghe, Jean Jacques Hauw, Julien Chapuis, Epidémiologie des maladies chroniques : impact des interactions gène environnement sur la santé des populations, Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé, Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Vlaams Instituut voor Biotechnologie [Ghent, Belgique] (VIB), Universiteit Gent = Ghent University (UGENT), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Médicaments et molécules pour agir sur les Systèmes Vivants - U 1177 (M2SV), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Institut de pharmacologie moléculaire et cellulaire (IPMC), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Mécanismes de la Tumorigénèse et Thérapies Ciblées - UMR 8161 (M3T), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), Réseau International des Instituts Pasteur (RIIP), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Service d'Hépato-gastro-entérologie [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), CEA [Fontenay-aux-Roses] (UGRA / SETA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Troubles cognitifs dégénératifs et vasculaires - U 1171 - EA 1046 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuropsychiatrie : recherche épidémiologique et clinique (PSNREC), Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institute of Brain, Behaviour and Mental Health, University of Manchester [Manchester], Hérard, Anne-Sophie, Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Troubles cognitifs dégénératifs et vasculaires - U 1171 (TCDV), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), CDithem Platform, IGM, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 (RNMCD), Institut Fédératif de Recherche 142, Institut Fédératif de Recherche, Center for Medical Genetics [Ghent], Ghent University Hospital, Département de neurologie, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Institut de biologie de Lille - IBL (IBLI), Université de Lille, Sciences et Technologies-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Université de Lille, Droit et Santé-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Division of Neuroscience and Experimental Psychology [Salford, UK], University of Manchester [Manchester]-Salford Royal NHS Foundation Trust [Salford, UK], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Dept Med Prot Res, Flanders Institute for Biotechnology, Département Imagerie et Simulation pour le Contrôle (DISC), Laboratoire d'Intégration des Systèmes et des Technologies (LIST), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Laboratoire des Maladies Neurodégénératives - UMR 9199 [LMN], Institut de pharmacologie moléculaire et cellulaire [IPMC], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 [JPArc], Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 [CIIL], Récepteurs nucléaires, maladies cardiovasculaires et diabète - U 1011 [RNMCD], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 [RID-AGE], Nutrition-Génétique et Exposition aux Risques Environnementaux [NGERE], CEA [Fontenay-aux-Roses] [UGRA / SETA], and Institut de biologie de Lille - IBL [IBLI]
Subjects: 0301 basic medicine, Patch-Clamp Techniques, ADAM, A Disintegrin and Metalloproteinase Domain, lcsh:Medicine, Cathepsin D, COFRADIC, combined fractional diagonal chromatography, ALPHA-SECRETASE, Mice, 0302 clinical medicine, Pepstatins, Amyloid precursor protein, BRAIN, RNA, Small Interfering, Tissues and Organs (q-bio.TO), GENE-EXPRESSION, lcsh:R5-920, ROLES, IRS4, insulin receptor substrate 4, P3 peptide, Brain, Long-term potentiation, General Medicine, AMYLOID PRECURSOR PROTEIN, Alpha secretase, BACE, Beta-site APP cleaving enzyme 1, Neurons and Cognition (q-bio.NC), [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], RNA Interference, Macrolides, LTP, lcsh:Medicine (General), GKAP1, G kinase-anchoring protein 1, Research Paper, Genetically modified mouse, Amyloid, CTSD, cathepsin D, Down-Regulation, Mice, Transgenic, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, TD2, Type 2 diabetes, Alzheimer Disease, APP, amyloid precursor protein, Cell Line, Tumor, Animals, Humans, Secretion, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, TRANSGENIC MOUSE MODEL, Amyloid beta-Peptides, PLA, proximity ligation assay, lcsh:R, LTP, long term potentiation, Biology and Life Sciences, Quantitative Biology - Tissues and Organs, ADAM30, DEGRADATION, CamKIIα, Ca2 +/calmodulin-dependent protein kinase II alpha, Molecular biology, Mice, Inbred C57BL, MICE, ADAM Proteins, 030104 developmental biology, HEK293 Cells, Metabolism, Microscopy, Fluorescence, Quantitative Biology - Neurons and Cognition, FOS: Biological sciences, COGNITIVE DECLINE, biology.protein, Alzheimer, BSA, bovine serum albumin, MMP, metalloproteinase, INHIBITORS, Lysosomes, APP, MRI, magnetic resonance imaging, 030217 neurology & neurosurgery
Abstract: Although several ADAMs (A disintegrin-like and metalloproteases) have been shown to contribute to the amyloid precursor protein (APP) metabolism, the full spectrum of metalloproteases involved in this metabolism remains to be established. Transcriptomic analyses centred on metalloprotease genes unraveled a 50% decrease in ADAM30 expression that inversely correlates with amyloid load in Alzheimer's disease brains. Accordingly, in vitro down- or up-regulation of ADAM30 expression triggered an increase/decrease in Aβ peptides levels whereas expression of a biologically inactive ADAM30 (ADAM30mut) did not affect Aβ secretion. Proteomics/cell-based experiments showed that ADAM30-dependent regulation of APP metabolism required both cathepsin D (CTSD) activation and APP sorting to lysosomes. Accordingly, in Alzheimer-like transgenic mice, neuronal ADAM30 over-expression lowered Aβ42 secretion in neuron primary cultures, soluble Aβ42 and amyloid plaque load levels in the brain and concomitantly enhanced CTSD activity and finally rescued long term potentiation alterations. Our data thus indicate that lowering ADAM30 expression may favor Aβ production, thereby contributing to Alzheimer's disease development., Highlights • By transcriptomic analyses, low levels of ADAM30 expression was observed in the brain of AD cases (compared with controls). • Activation of cathepsin D by ADAM30 is required to modulate the APP metabolism in vitro, i.e. decrease in Ab secretion. • In AD-like mice, neuronal ADAM30 expression led to lower soluble Aβ42, amyloid plaques and to rescue long term potentiation The amyloid precursor protein (APP) processing is central in the etiology of Alzheimer's disease (AD). Characterizing the actors of this metabolism is thus an important challenge. We searched for proteins involved in the APP processing and we selected the A disintegrin-like and metalloprotease 30 (ADAM30). Our results revealed an axis in APP metabolism pathway through an ADAM30-dependent cathepsin D activation. When activated following ADAM30 expression, a decrease in Aβ secretion occurred in vitro and in vivo. ADAM30 under-expression observed in AD brains and thus the impairment of the ADAM30-dependent pathway may favor Aβ peptide production and, ultimately, AD development.
Published: 2016

21. Mitotic index, microvascular proliferation, and necrosis define 3 pathological subgroups of prognostic relevance among 1p/19q co-deleted anaplastic oligodendrogliomas

Author: Figarella-Branger, Dominique, Mokhtari, Karima, Dehais, Caroline, Carpentier, Catherine, Colin, Carole, Jouvet, Anne, Uro-Coste, Emmanuelle, Forest, Fabien, Maurage, Claude-Alain, Vignaud, Jean-Michel, Polivka, Marc, Lechapt-Zalcman, Emmanuèle, Eimer, Sandrine, Viennet, Gabriel, Quintin-Roué, Isabelle, Aubriot-Lorton, Marie-Hélène, Diebold, Marie-Danièle, Loussouarn, Delphine, Lacroix, Catherine, Rigau, Valérie, Laquerrière, Annie, Vandenbos, Fanny, Michalak, Sophie, Sevestre, Henri, Peoc'H, Michel, Labrousse, François, Christov, Christo, Kemeny, Jean-Louis, Chenard, Marie-Pierre, Chiforeanu, Danchristian, Ducray, François, Idbaih, Ahmed, Delattre, Jean-Yves, Network, POLA, Service d’Anatomie Pathologique et de Neuropathologie, APHM, Hôpital de la Timone, Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Service de neurologie 2 [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre de Pathologie et de Neuropathologie Est, Hospices Civils de Lyon (HCL), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service d'Anatomie et de Cytologie Pathologique, CHU Saint-Etienne-Hôpital Bellevue, Service d'Anatomie Pathologique, Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service d’Anatomie Pathologique [CHRU Nancy], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Nutrition-Génétique et Exposition aux Risques Environnementaux (NGERE), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lorraine (UL), Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Hôpital Côte de Nacre [CHU Caen], CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), CHU de Bordeaux Pellegrin [Bordeaux], Histologie et Pathologie Moléculaire des Tumeurs, Université Bordeaux Segalen - Bordeaux 2-EA 2406, Hôpital Jean Minjoz, Centre Hospitalier Régional Universitaire [Besançon] (CHRU Besançon), Hôpital de la Cavale Blanche - CHRU Brest (CHU - BREST ), Service d'anatomie et de cytologie pathologiques, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Hôpital Robert Debré, Hôpital Guillaume-et-René-Laennec [Saint-Herblain], AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Laboratoire d'anatomie cytologie pathologiques, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [Montpellier], Service d'Anatomie et Cytologie Pathologique [Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Centre Hospitalier Universitaire de Nice (CHU Nice), Département de pathologie cellulaire et tissulaire, CHU d'Angers, 4, rue Larrey, 49100 Angers, France., Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM)-PRES Université Nantes Angers Le Mans (UNAM), Service d'anatomie et cytopathologie, CHU Amiens-Picardie, Service d'Anatomie Pathologique [CHU Limoges], CHU Limoges, CHU Henri Mondor, CHU Clermont-Ferrand, Service d'Anatomie Pathologique Générale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], Service d'anatomie et cytologie pathologiques [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Hôpital Pontchaillou-CHU Pontchaillou [Rennes], Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Centre de Recherche en Cancérologie de Lyon (CRCL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre Léon Bérard [Lyon]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], Service d'anatomie et cytologie pathologiques [Rennes] = Anatomy and Cytopathology [Rennes], CHU Pontchaillou [Rennes], Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne] (CHU ST-E), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Hôpital Gui de Chauliac [CHU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Henri Mondor [Créteil], Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Aix Marseille Université (AMU), Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)
Subjects: microvascular proliferation, Male, Cancer Research, Pathology, medicine.medical_specialty, Mitotic index, Necrosis, [SDV]Life Sciences [q-bio], Oligodendroglioma, Anaplastic oligodendroglioma, 1p/19q co-deletion, 03 medical and health sciences, 0302 clinical medicine, medicine, Mitotic Index, Humans, mitoses, Survival rate, Mitosis, Pathological, Letter to the Editor, Neovascularization, Pathologic, business.industry, Brain Neoplasms, Middle Aged, medicine.disease, Prognosis, Isocitrate Dehydrogenase, 3. Good health, Survival Rate, Isocitrate dehydrogenase, Oncology, Chromosomes, Human, Pair 1, 030220 oncology & carcinogenesis, Female, Neurology (clinical), anaplastic oligodendrogliomas, medicine.symptom, Chromosome Deletion, business, Chromosomes, Human, Pair 19, 030217 neurology & neurosurgery
Abstract: CERVOXY COLL; International audience
Published: 2016

22. Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease

Author: Valérie Suain, Véronique Sazdovitch, Charles Duyckaerts, Mounir Belkouch, Jean Pierre Brion, Marième Ndjim, Kunie Ando, Karen Tomimura, Marie-Claude Potier, Michèle Authelet, Zehra Yilmaz, Cristina Vergara, Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire d'histologie générale, de neuroanatomie et de neuropathologie [Bruxelles], Université libre de Bruxelles (ULB), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), and HAL-UPMC, Gestionnaire
Subjects: 0301 basic medicine, Diffuse Lewy body disease, Pathology, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Autophagy-Related Proteins, Pick disease, PICALM, 0302 clinical medicine, PSEN1, LC3, Corticobasal degeneration, Phosphorylation, FTLD-MAPT, Neurons, Brain, Pneumothorax, Neurofibrillary Tangles, Frontotemporal lobar degeneration, Alzheimer's disease, Endocytosis, FTLD-TDP, Neurology, Tauopathies, Monomeric Clathrin Assembly Proteins, Beclin-1, Supranuclear Palsy, Progressive, medicine.medical_specialty, Single-nucleotide polymorphism, tau Proteins, Biology, lcsh:RC321-571, Progressive supranuclear palsy, 03 medical and health sciences, Pick Disease of the Brain, Alzheimer Disease, mental disorders, NFTs, medicine, Genetic predisposition, Autophagy, Humans, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, Clathrin, 030104 developmental biology, Frontotemporal Lobar Degeneration, Tau, 030217 neurology & neurosurgery
Abstract: International audience; Single nucleotide polymorphisms in PICALM, a key component of clathrin-mediated endocytosis machinery, have been identified as genetic susceptibility loci for late onset Alzheimer's disease (LOAD). We previously reported that PICALM protein levels were decreased in AD brains and that PICALM was co-localised with neurofibrillary tangles in LOAD, familial AD with PSEN1 mutations and Down syndrome. In the present study, we analysed PICALM expression, cell localisation and association with pathological cellular inclusions in other tauopathies and in non-tau related neurodegenerative diseases. We observed that PICALM was associated with neuronal tau pathology in Pick disease and in progressive supranuclear palsy (PSP) and co-localised with both 3R and 4R tau positive inclusions unlike in corticobasal degeneration (CBD) or in frontotemporal lobar degeneration (FTLD)-MAPT P301L. PICALM immunoreactivities were not detected in tau-positive tufted astrocytes in PSP, astrocytic plaques in CBD, Lewy bodies in Lewy body disease, diffuse type (LBD) and in TDP-43-positive inclusions in FTLD. In the frontal cortex in tauopathies, the ratio of insoluble to soluble PICALM was increased while the level of soluble PICALM was decreased and was inversely correlated with the level of phosphotau. PICALM decrease was also significantly correlated with increased LC3-II and decreased Beclin-1 levels in tauopathies and in non-tau related neurodegenerative diseases. These results suggest that there is a close relationship between abnormal PICALM processing, tau pathology and impairment of autophagy in human neurodegenerative diseases.
Published: 2016

23. Prognostic impact of the 2016 WHO classification of diffuse gliomas in the French POLA cohort

Author: Dominique Figarella-Branger, Anh Tuan Nguyen, Hugues Loiseau, Jean-Yves Delattre, Claude-Alain Maurage, Olivier Chinot, François Ducray, Carole Colin, Ahmed Idbaih, Elisabeth Moyal, Emmanuelle Uro-Coste, Emmanuèle Lechapt-Zalcman, Caroline Dehais, Catherine Carpentier, Christine Desenclos, Emeline Tabouret, Karima Mokhtari, Anne Jouvet, David Meyronet, Marc Polivka, Neuro-Oncologie [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Centre de Recherches en Oncologie biologique et Oncopharmacologie (CRO2), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomo-Cyto-Pathologie et de NeuroPathologie [Hôpital de la Timone - APHM] (ACPNP), Aix Marseille Université (AMU)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Pitié-Salpêtrière [APHP], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique (CNRS), Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Laboratoire d'anatomie et de cytopathologie - Centre hospitalier Lyon Sud, CHU Toulouse [Toulouse], Faculté de Médecine [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse], CHU de Bordeaux Pellegrin [Bordeaux], Institut Claudius Regaud, CRLCC Institut Claudius Regaud, Centre de Recherches en Cancérologie de Toulouse (CRCT), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Fédérale Toulouse Midi-Pyrénées, Service de pathologie [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Service de pathologie, AP-HP Hôpital Lariboisière [Paris], Laboratoire d'Anatomie Pathologique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Imagerie et Stratégies Thérapeutiques des pathologies Cérébrales et Tumorales (ISTCT), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Service de neurochirurgie, Hôpital Nord - Amiens, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Université de Toulouse (UT)-Université de Toulouse (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT), Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Normandie Université (NU)-Normandie Université (NU)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: Oncology, Adult, Male, medicine.medical_specialty, Pathology, IDH1, Adolescent, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Oligodendroglioma, [SDV.CAN]Life Sciences [q-bio]/Cancer, 1p/19q Codeletion, Astrocytoma, World Health Organization, Disease-Free Survival, Pathology and Forensic Medicine, Cohort Studies, 03 medical and health sciences, Cellular and Molecular Neuroscience, Young Adult, 0302 clinical medicine, Internal medicine, medicine, Humans, Oligodendroglial Tumor, neoplasms, Pathological, Grading (tumors), Aged, Aged, 80 and over, business.industry, Brain Neoplasms, Glioma, Middle Aged, medicine.disease, Prognosis, 3. Good health, 030220 oncology & carcinogenesis, Cohort, Mutation, Female, Neurology (clinical), Who classification, business, 030217 neurology & neurosurgery, Anaplastic astrocytoma
Abstract: The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50.4 years (range 17.1–84.4). Based on the new histomolecular classification, diagnoses included anaplastic oligodendroglioma IDH mutant and 1p/19q-codeleted (32.5 %), anaplastic astrocytoma IDH mutant (IDH mut) (11.0 %), anaplastic astrocytoma IDH wild type (IDH wt) (5.3 %), glioblastoma IDH mut (17.1 %), and glioblastoma IDH wt (33.2 %). Ten patients presented with a diffuse midline tumor, H3 K27M mutant. The new WHO classification was prognostic for progression-free survival (PFS) and overall survival (OS) (p
Published: 2016

24. Extensive brain demyelinating lesions under natalizumab: The role of anti-natalizumab antibodies

Author: Damien Galanaud, Catherine Lubetzki, Christine Stadelmann, Rabab Debs, Robert Fahed, E. Maillart, Caroline Papeix, Charles Duyckaerts, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Service de Neuroradiologie [CHU Pitié-Salpêtrière], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Adult, Pathology, medicine.medical_specialty, Immunologic Factors, medicine.drug_class, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Monoclonal antibody, Antibodies, 03 medical and health sciences, Multiple Sclerosis, Relapsing-Remitting, 0302 clinical medicine, Natalizumab, medicine, Humans, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, medicine.diagnostic_test, biology, business.industry, Multiple sclerosis, Progressive multifocal leukoencephalopathy, Brain, Magnetic resonance imaging, medicine.disease, Magnetic Resonance Imaging, 3. Good health, Discontinuation, biology.protein, Female, Neurology (clinical), Antibody, business, 030217 neurology & neurosurgery, medicine.drug
Abstract: Natalizumab (NZ), a humanized anti-α4 integrin monoclonal antibody, is used in the treatment of highly active multiple sclerosis (MS). Progressive multifocal leukoencephalopathy (PML) and rare cases of primary CNS lymphoma1 have been reported in NZ-treated patients, whereas severe relapses with MS reactivation are described after NZ discontinuation.
Published: 2015

25. CYP46A1 inhibition, brain cholesterol accumulation and neurodegeneration pave the way for Alzheimer’s disease

Author: Dominique Langui, Michel Vidaud, Eloise Hudry, Nathalie Cartier, Ivan Bièche, Marc Dhenain, Sandro Alves, Olivier Laprévote, Patrick Aubourg, Sophie Ayciriex, Charles Duyckaerts, Jérôme Braudeau, Catherine Marquer, Nicolas Auzeil, Farah Chali, Marie-Claude Potier, Richard B. Miles, Fathia Djelti, Jennifer Varin, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Institut des Sciences Analytiques (ISA), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Université de Lyon, Mécanismes adaptatifs : des organismes aux communautés, Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Thérapie génique, Génomique et Epigénomique (U 1169), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), Service MIRCEN (MIRCEN), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Centre National de la Recherche Scientifique (CNRS), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux (EA 7331), Facultés des sciences pharmaceutiques et biologiques, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux (Inserm U745), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement (IFR71), Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Inserm U986, Institut National de la Santé et de la Recherche Médicale (INSERM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Institut de Biologie François JACOB (JACOB), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Mécanismes adaptatifs : des organismes aux communautés ( MECADEV ), Muséum National d'Histoire Naturelle ( MNHN ) -Centre National de la Recherche Scientifique ( CNRS ), Thérapie génique, Génomique et Epigénomique ( U 1169 ), Université Paris-Saclay-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Sud - Paris 11 ( UP11 ), Laboratoire des Maladies Neurodégénératives - UMR 9199 ( LMN ), Université Paris-Sud - Paris 11 ( UP11 ) -Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Centre National de la Recherche Scientifique ( CNRS ), Génétique, physiopathologie et approches thérapeutiques des maladies héréditaires du système nerveux ( EA 7331 ), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière ( CRICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Toxicologie, Pharmacologie et Signalisation Cellulaire ( U1124 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -CHU Pitié-Salpêtrière [APHP]-Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Genetique et Biotherapies des Maladies Degeneratives et Proliferatives du Systeme Nerveux ( Inserm U745 ), Institut des sciences du Médicament -Toxicologie - Chimie - Environnement ( IFR71 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Ecole Nationale Supérieure de Chimie de Paris- Chimie ParisTech-PSL ( ENSCP ) -Centre National de la Recherche Scientifique ( CNRS ) -Institut de Recherche pour le Développement ( IRD ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Institut National de la Santé et de la Recherche Médicale, Service MIRCEN ( MIRCEN ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Chimie du CNRS (INC)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Institut de Biologie François JACOB (JACOB), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Ecole Nationale Supérieure de Chimie de Paris - Chimie ParisTech-PSL (ENSCP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD)-Université Paris Descartes - Paris 5 (UPD5)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Hippocampus, Hippocampal formation, Small hairpin RNA, chemistry.chemical_compound, Amyloid beta-Protein Precursor, 0302 clinical medicine, [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], RNA interference, Homeostasis, Enzyme Inhibitors, [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Lipid raft, ComputingMilieux_MISCELLANEOUS, Neurons, 0303 health sciences, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Neurodegeneration, Brain, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Cholesterol, [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Female, medicine.medical_specialty, Mice, Transgenic, Biology, 03 medical and health sciences, Alzheimer Disease, [CHIM.ANAL]Chemical Sciences/Analytical chemistry, Internal medicine, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], medicine, Cholesterol 24-Hydroxylase, Animals, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Liver X receptor, 030304 developmental biology, Amyloid beta-Peptides, medicine.disease, Mice, Inbred C57BL, Endocrinology, chemistry, Steroid Hydroxylases, [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: Abnormalities in neuronal cholesterol homeostasis have been suspected or observed in several neurodegenerative disorders including Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has not been demonstrated whether an increased abundance of cholesterol in neurons in vivo contributes to neurodegeneration. To address this issue, we used RNA interference methodology to inhibit the expression of cholesterol 24-hydroxylase, encoded by the Cyp46a1 gene, in the hippocampus of normal mice. Cholesterol 24-hydroxylase controls cholesterol efflux from the brain and thereby plays a major role in regulating brain cholesterol homeostasis. We used an adeno-associated virus vector encoding short hairpin RNA directed against the mouse Cyp46a1 mRNA to decrease the expression of the Cyp46a1 gene in hippocampal neurons of normal mice. This increased the cholesterol concentration in neurons, followed by cognitive deficits and hippocampal atrophy due to apoptotic neuronal death. Prior to neuronal death, the recruitment of the amyloid protein precursor to lipid rafts was enhanced leading to the production of β-C-terminal fragment and amyloid-β peptides. Abnormal phosphorylation of tau and endoplasmic reticulum stress were also observed. In the APP23 mouse model of Alzheimer's disease, the abundance of amyloid-β peptides increased following inhibition of Cyp46a1 expression, and neuronal death was more widespread than in normal mice. Altogether, these results suggest that increased amounts of neuronal cholesterol within the brain may contribute to inducing and/or aggravating Alzheimer's disease.
Published: 2015

26. Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer’s disease patients

Author: Charles Duyckaerts, Malaplate-Armand C, Olivier Jl, Marie-Claude Potier, Isabelle Rivals, Marie Sarazin, Michel Bottlaender, Lorraine Hamelin, Hélène Corne, Julien Lagarde, Luce Dauphinot, Bruno Dubois, Kunie Ando, Guillaume Dorothée, G. Fontaine, Cossec Jc, Fabian Corlier, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Equipe de Statistique Appliquée, Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI ParisTech), Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Pathologies biliaires, fibrose et cancer du foie (Inserm UMR_S 938), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [APHP], Unité de Recherches Animal et Fonctionnalités des Produits Animaux (URAFPA), Institut National de la Recherche Agronomique (INRA)-Université de Lorraine (UL), Laboratoire de Biochimie et Biologie Moléculaire, Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Equipe de Statistique Appliquée (UMRS 1158) (ESA), Ecole Superieure de Physique et de Chimie Industrielles de la Ville de Paris (ESPCI Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique (UMRS 1158), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Pathologies biliaires, fibrose et cancer du foie, Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], HAL-UPMC, Gestionnaire, Centre de Psychiatrie et Neurosciences (U894), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Neurophysiologie Respiratoire Expérimentale et Clinique, CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre de Recherche Saint-Antoine (UMRS893), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Ecole Supérieure de Physique et de Chimie Industrielles de la Ville de Paris ( ESPCI ParisTech ), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Pathologies biliaires, fibrose et cancer du foie ( Inserm UMR_S 938 ), Centre de Recherche Saint-Antoine ( CR Saint-Antoine ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ) -CHU Saint-Antoine [APHP], Unité de Recherches Animal et Fonctionnalités des Produits Animaux ( URAFPA ), Université de Lorraine ( UL ) -Institut National de la Recherche Agronomique ( INRA ), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] ( IM2A ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Institut d'Imagerie BioMédicale ( I2BM ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, and CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC )
Subjects: Apolipoprotein E, Male, Pathology, [ SDV.MHEP.PSM ] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, [SDV.MHEP.PSM] Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Amyloid beta-Peptides -- cerebrospinal fluid, 0302 clinical medicine, Cerebrospinal fluid, Apolipoproteins E -- genetics, Biomarkers -- blood -- cerebrospinal fluid -- metabolism, Aged, 80 and over, 0303 health sciences, Microscopy, Confocal, Sciences bio-médicales et agricoles, Middle Aged, 3. Good health, Psychiatry and Mental health, Endosomes -- pathology, Biomarker (medicine), Original Article, Female, medicine.medical_specialty, Amyloid, Fibroblasts -- pathology, Endosome, Immunocytochemistry, Neuroimaging, tau Proteins, Endosomes, Peripheral blood mononuclear cell, Cognitive Dysfunction -- blood -- diagnosis -- physiopathology, 03 medical and health sciences, Cellular and Molecular Neuroscience, Apolipoproteins E, Alzheimer Disease, medicine, Dementia, Humans, Cognitive Dysfunction, Biological Psychiatry, 030304 developmental biology, Aged, Leukocytes, Mononuclear -- physiology, Amyloid beta-Peptides, business.industry, tau Proteins -- cerebrospinal fluid, Médecine pathologie humaine, Fibroblasts, medicine.disease, Case-Control Studies, Positron-Emission Tomography, [SDV.MHEP.PSM]Life Sciences [q-bio]/Human health and pathology/Psychiatrics and mental health, Leukocytes, Mononuclear, Alzheimer Disease -- blood -- diagnosis -- pathology, business, 030217 neurology & neurosurgery, Biomarkers
Abstract: Identification of blood-based biomarkers of Alzheimer's disease (AD) remains a challenge. Neuropathological studies have identified enlarged endosomes in post-mortem brains as the earliest cellular change associated to AD. Here the presence of enlarged endosomes was investigated in peripheral blood mononuclear cells from 48 biologically defined AD patients (25 with mild cognitive impairment and 23 with dementia (AD-D)), and 23 age-matched healthy controls using immunocytochemistry and confocal microscopy. The volume and number of endosomes were not significantly different between AD and controls. However, the percentage of cells containing enlarged endosomes was significantly higher in the AD-D group as compared with controls. Furthermore, endosomal volumes significantly correlated to [C(11)]PiB cortical index measured by positron emission tomography in the AD group, independently of the APOE genotype, but not to the levels of amyloid-beta, tau and phosphorylated tau measured in the cerebrospinal fluid. Importantly, we confirmed the presence of enlarged endosomes in fibroblasts from six unrelated AD-D patients as compared with five cognitively normal controls. This study is the first, to our knowledge, to report morphological alterations of the endosomal compartment in peripheral cells from AD patients correlated to amyloid load that will now be evaluated as a possible biomarker., info:eu-repo/semantics/published
Published: 2015

27. Quantifying the heritability of glioma using genome-wide complex trait analysis

Author: Kinnersley, Ben, Mitchell, Jonathan S., Gousias, Konstantinos, Schramm, Johannes, Idbaih, Ahmed, Labussière, Marianne, Marie, Yannick, Rahimian, Amithys, Wichmann, H.-Erich, Schreiber, Stefan, Hoang-Xuan, Khe, Delattre, Jean-Yves, Nöthen, Markus M, Mokhtari, Karima, Lathrop, Mark, Bondy, Melissa, Simon, Matthias, Sanson, Marc, Houlston, Richard, HAL UPMC, Gestionnaire, The Institute of Cancer Research, University of Bonn Medical Center, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), OncoNeuroTek [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Universitätsklinikum Schleswig-Holstein, Christian-Albrechts-Universität zu Kiel (CAU), Rheinische Friedrich-Wilhelms-Universität Bonn, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Fondation Jean Dausset CEPH, McGill University = Université McGill [Montréal, Canada], Baylor College of Medicine (BCM), Baylor University, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Helmholtz-Zentrum München (HZM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], and Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Adult, Quantitative Trait, Heritable, Brain Neoplasms, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Humans, Glioma, Middle Aged, Polymorphism, Single Nucleotide, Article, Genome-Wide Association Study, Retrospective Studies
Abstract: International audience; Genome-wide association studies (GWAS) have successfully identified a number of common single-nucleotide polymorphisms (SNPs) influencing glioma risk. While these SNPs only explain a small proportion of the genetic risk it is unclear how much is left to be detected by other, yet to be identified, common SNPs. Therefore, we applied Genome-Wide Complex Trait Analysis (GCTA) to three GWAS datasets totalling 3,373 cases and 4,571 controls and performed a meta-analysis to estimate the heritability of glioma. Our results identify heritability estimates of 25% (95% CI: 20–31%, P = 1.15 × 10 −17) for all forms of glioma-26% (95% CI: 17–35%, P = 1.05 × 10 −8) for glioblastoma multiforme (GBM) and 25% (95% CI: 17–32%, P = 1.26 × 10 −10) for non-GBM tumors. This is a substantial increase from the genetic variance identified by the currently identified GWAS risk loci (~6% of common heritability), indicating that most of the heritable risk attributable to common genetic variants remains to be identified.
Published: 2015

28. Mise au point d'une antenne IRM 11.7T pour l'imagerie directe de coupes histologiques

Author: Bertrand, Anne, Hoang, Dung, Petiet, Alexandra, Delatour, Benoit, Duyckaerts, Charles, Sazdovitch, Véronique, Wadghiri, youssef Z., Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Algorithms, models and methods for images and signals of the human brain (ARAMIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Inria de Paris, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), New York University School of Medicine (NYU), New York University School of Medicine, NYU System (NYU)-NYU System (NYU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Centre de Neuro-Imagerie de Recherche (CENIR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Center for NeuroImaging Research-Human MRI Neuroimaging core facility for clinical research [ICM Paris] (CENIR), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)-Inria de Paris, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)
Subjects: [SDV.MHEP.OS]Life Sciences [q-bio]/Human health and pathology/Sensory Organs, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2015

29. Detection, characterization and inhibition of FGFR-TACC fusions in IDH wild type glioma

Author: Josep Tabernero, Jennifer A. Chan, Blandine Boisselier, Julien Savatovsky, Kevin Petrecca, Anna Lasorella, Aurélie Kamoun, Gaetano Finocchiaro, Hayat Belaid, Alessandra Fucci, Antonio Iavarone, Mehdi Touat, Feng R. Luo, Yannick Marie, Anna Luisa Di Stefano, Marc Sanson, Rosina Paterra, Marica Eoli, Marine Giry, Stephen Yip, Karima Mokhtari, Jean-Charles Soria, Ahmed Idbaih, Veronique Frattini, Aurelie Bruno, Caroline Houillier, Marianne Labussière, Pietro Zoppoli, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Service de neurologie 2 [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Dpt of Brain and Behavioral Sciences [Pavia], University of Pavia, Institute for Cancer Genetics, Columbia University Irving Medical Center (CUIMC), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Pavia = University of Pavia (UNIPV), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Di Stefano, Al, Fucci, A, Frattini, V, Labussiere, M, Mokhtari, K, Zoppoli, P, Marie, Y, Bruno, A, Boisselier, B, Giry, M, Savatovsky, J, Touat, M, Belaid, H, Kamoun, A, Idbaih, A, Houillier, C, Luo, Fr, Soria, Jc, Tabernero, J, Eoli, M, Paterra, R, Yip, S, Petrecca, K, Chan, Ja, Finocchiaro, G, Lasorella, A, Sanson, M, and Iavarone, A.
Subjects: musculoskeletal diseases, Male, Cancer Research, IDH1, Oncogene Proteins, Fusion, FGFR Inhibition, DNA Mutational Analysis, Fluorescent Antibody Technique, Mice, Nude, [SDV.CAN]Life Sciences [q-bio]/Cancer, Antineoplastic Agents, Kaplan-Meier Estimate, Biology, Article, Mice, Glioma, Quinoxalines, medicine, Receptor, Fibroblast Growth Factor, Type 3, Animals, Humans, Molecular Targeted Therapy, Reverse Transcriptase Polymerase Chain Reaction, Brain Neoplasms, Wild type, medicine.disease, Fusion protein, Molecular biology, Immunohistochemistry, Xenograft Model Antitumor Assays, Isocitrate Dehydrogenase, 3. Good health, Oncology, Fibroblast growth factor receptor, Pyrazoles, Female, Microtubule-Associated Proteins, Immunostaining
Abstract: Purpose: Oncogenic fusions consisting of fibroblast growth factor receptor (FGFR) and TACC are present in a subgroup of glioblastoma (GBM) and other human cancers and have been proposed as new therapeutic targets. We analyzed frequency and molecular features of FGFR–TACC fusions and explored the therapeutic efficacy of inhibiting FGFR kinase in GBM and grade II and III glioma. Experimental Design: Overall, 795 gliomas (584 GBM, 85 grades II and III with wild-type and 126 with IDH1/2 mutation) were screened for FGFR–TACC breakpoints and associated molecular profile. We also analyzed expression of the FGFR3 and TACC3 components of the fusions. The effects of the specific FGFR inhibitor JNJ-42756493 for FGFR3–TACC3–positive glioma were determined in preclinical experiments. Two patients with advanced FGFR3–TACC3–positive GBM received JNJ-42756493 and were assessed for therapeutic response. Results: Three of 85 IDH1/2 wild-type (3.5%) but none of 126 IDH1/2-mutant grade II and III gliomas harbored FGFR3–TACC3 fusions. FGFR–TACC rearrangements were present in 17 of 584 GBM (2.9%). FGFR3–TACC3 fusions were associated with strong and homogeneous FGFR3 immunostaining. They are mutually exclusive with IDH1/2 mutations and EGFR amplification, whereas they co-occur with CDK4 amplification. JNJ-42756493 inhibited growth of glioma cells harboring FGFR3–TACC3 in vitro and in vivo. The two patients with FGFR3–TACC3 rearrangements who received JNJ-42756493 manifested clinical improvement with stable disease and minor response, respectively. Conclusions: RT-PCR sequencing is a sensitive and specific method to identify FGFR–TACC–positive patients. FGFR3–TACC3 fusions are associated with uniform intratumor expression of the fusion protein. The clinical response observed in the FGFR3–TACC3–positive patients treated with an FGFR inhibitor supports clinical studies of FGFR inhibition in FGFR–TACC–positive patients. Clin Cancer Res; 21(14); 3307–17. ©2015 AACR. See related commentary by Ahluwalia and Rich, p. 3105
Published: 2015

30. TCF12 is mutated in anaplastic oligodendroglioma

Author: Labreche, Karim, Simeonova, Iva, Kamoun, Aurélie, Gleize, Vincent, Chubb, Daniel, Letouzé, Eric, Riazalhosseini, Yasser, Dobbins, Sara E., Elarouci, Nabila, Ducray, Francois, De Reyniès, Aurélien, Zelenika, Diana, Wardell, Christopher P., Frampton, Mathew, Saulnier, Olivier, Pastinen, Tomi, Hallout, Sabrina, Figarella-Branger, Dominique, Dehais, Caroline, Idbaih, Ahmed, Mokhtari, Karima, Delattre, Jean-Yves, Huillard, Emmanuelle, Lathrop, G Mark, Sanson, Marc, Houlston, Richard S., Institute of Cancer Research, Belmont, Sutton, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Ligue Nationale Contre le Cancer - Paris, Ligue Nationnale Contre le Cancer, McGill University = Université McGill [Montréal, Canada], Centre de recherche en neurosciences de Lyon (CRNL), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre National de Génotypage (CNG), Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Hôpital de la Timone [CHU - APHM] (TIMONE), Université de la Méditerranée - Aix-Marseille 2, UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Ligue Nationale Contre le Cancer (LNCC), Centre de recherche en neurosciences de Lyon - Lyon Neuroscience Research Center (CRNL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], and HAL UPMC, Gestionnaire
Subjects: Transcriptional Activation, [SDV.GEN]Life Sciences [q-bio]/Genetics, Brain Neoplasms, Mutation, Oligodendroglioma, Basic Helix-Loop-Helix Transcription Factors, Down-Regulation, Humans, [SDV.GEN] Life Sciences [q-bio]/Genetics, Article
Abstract: Anaplastic oligodendroglioma (AO) are rare primary brain tumours that are generally incurable, with heterogeneous prognosis and few treatment targets identified. Most oligodendrogliomas have chromosomes 1p/19q co-deletion and an IDH mutation. Here we analysed 51 AO by whole-exome sequencing, identifying previously reported frequent somatic mutations in CIC and FUBP1. We also identified recurrent mutations in TCF12 and in an additional series of 83 AO. Overall, 7.5% of AO are mutated for TCF12, which encodes an oligodendrocyte-related transcription factor. Eighty percent of TCF12 mutations identified were in either the bHLH domain, which is important for TCF12 function as a transcription factor, or were frameshift mutations leading to TCF12 truncated for this domain. We show that these mutations compromise TCF12 transcriptional activity and are associated with a more aggressive tumour type. Our analysis provides further insights into the unique and shared pathways driving AO., Anaplastic oligodendrogliomas are rare and incurable primary brain tumours with few treatment options. Here Labreche et al. perform whole-exome sequencing and identify recurring mutations in transcription factor TCF12, which are associated with aggressive tumours.
Published: 2015

31. Genome-wide association study identifies multiple susceptibility loci for glioma

Author: Kinnersley, Ben, Labussière, Marianne, Holroyd, Amy, Di Stefano, Anna-Luisa, Broderick, Peter, Vijayakrishnan, Jayaram, Mokhtari, Karima, Delattre, Jean-Yves, Gousias, Konstantinos, Schramm, Johannes, Schoemaker, Minouk J., Fleming, Sarah J., Herms, Stefan, Heilmann, Stefanie, Schreiber, Stefan, Wichmann, Heinz-Erich, Nöthen, Markus M., Swerdlow, Anthony, Lathrop, Mark, Simon, Matthias, Bondy, Melissa, Sanson, Marc, Houlston, Richard S., The Institute of Cancer Research, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Microsoft Research [Redmond], Microsoft Corporation [Redmond, Wash.], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Division of genetics and epidemiology, The institute of cancer research [London], Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Bonn Medical Center, Department of Genomics, Institute of Human Genetics [Erlangen, Allemagne], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Christian-Albrechts-Universität zu Kiel (CAU), Helmholtz Zentrum München = German Research Center for Environmental Health, Ludwig-Maximilians-Universität München (LMU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Rheinische Friedrich-Wilhelms-Universität Bonn, Fondation Jean Dausset CEPH, McGill University = Université McGill [Montréal, Canada], Laboratoire de Chimie Physique - Matière et Rayonnement (LCPMR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Baylor College of Medicine (BCM), Baylor University, Institute of Cancer Research, Belmont, Sutton, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Helmholtz-Zentrum München (HZM), Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neurologie 1 [CHU Pitié-Salpétrière], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: Male, Biological sciences, Genotype, Genetics, Humans, Female, Genetic Predisposition to Disease, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Glioma, Middle Aged, Article, Genome-Wide Association Study
Abstract: Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B, P=3.02 × 10−9) and non-GBM at 10q25.2 (rs11196067, near VTI1A, P=4.32 × 10−8), 11q23.2 (rs648044, near ZBTB16, P=6.26 × 10−11), 12q21.2 (rs12230172, P=7.53 × 10−11) and 15q24.2 (rs1801591, near ETFA, P=5.71 × 10−9). Our findings provide further insights into the genetic basis of the different glioma subtypes., Using meta-analysis of previous genome-wide association studies against the latest reference variant databases, this work identifies five new risk loci for glioblastoma and non-glioblastoma type of glioma.
Published: 2015

32. A Recurrent Mutation in CACNA1G Alters Cav3.1 T-Type Calcium-Channel Conduction and Causes Autosomal-Dominant Cerebellar Ataxia

Author: Anna Castrioto, Charles Duyckaerts, Alfredo Brusco, Iulia Blesneac, Marie Coutelier, Emeline Mundwiller, Giovanni Stevanin, Marie Lorraine Monin, Alexis Brice, Philippe Lory, Alexandra Durr, Mathieu Anheim, Isabelle Le Ber, Kunie Ando, Arnaud Monteil, Laboratory of Human Molecular Genetics, Université Catholique de Louvain = Catholic University of Louvain (UCL)-de Duve Institute, École pratique des hautes études (EPHE), Université Paris sciences et lettres (PSL), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de Génomique Fonctionnelle - Montpellier GenomiX (IGF MGX), Institut de Génomique Fonctionnelle (IGF), Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Montpellier 2 - Sciences et Techniques (UM2)-Centre National de la Recherche Scientifique (CNRS), LabEx Ion Channel Science and Therapeutics, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Department of Medical Sciences, Università degli studi di Torino (UNITO), Medical Genetics Unit, 'Città della Salute e della Scienza' Hospital, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération de Médecine Translationnelle de Strasbourg (FMTS), Université de Strasbourg (UNISTRA), Département de Neurologie - Hôpital de Hautepierre, Unité Médicale des Troubles du Mouvement, CHU Grenoble-Clinique de Neurologie, Fonctions cérébrales et neuromodulation, [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), École Pratique des Hautes Études (EPHE), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-BioCampus (BCM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli studi di Torino = University of Turin (UNITO), HAL-UPMC, Gestionnaire, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Male, Cerebellum, Purkinje cell, Deep cerebellar nuclei, medicine.disease_cause, Calcium Channels, T-Type, Purkinje Cells, 0302 clinical medicine, Autosomal dominant cerebellar ataxia, Genetics(clinical), Child, Genetics (clinical), Genes, Dominant, Neurons, Genetics, 0303 health sciences, Mutation, Voltage-dependent calcium channel, Middle Aged, Pedigree, Electrophysiology, Phenotype, medicine.anatomical_structure, CACNA1G, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, Adolescent, Cerebellar Ataxia, cerebellum, Molecular Sequence Data, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Young Adult, 03 medical and health sciences, CACNA1G, ataxia, SCA, cerebellum, calcium channel, Report, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Amino Acid Sequence, Aged, 030304 developmental biology, Sequence Homology, Amino Acid, Cerebellar ataxia, ataxia, T-type calcium channel, medicine.disease, SCA, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Calcium, calcium channel, 030217 neurology & neurosurgery
Abstract: International audience; Hereditary cerebellar ataxias (CAs) are neurodegenerative disorders clinically characterized by a cerebellar syndrome, often accompanied by other neurological or non-neurological signs. All transmission modes have been described. In autosomal-dominant CA (ADCA), mutations in more than 30 genes are implicated, but the molecular diagnosis remains unknown in about 40% of cases. Implication of ion channels has long been an ongoing topic in the genetics of CA, and mutations in several channel genes have been recently connected to ADCA. In a large family affected by ADCA and mild pyramidal signs, we searched for the causative variant by combining linkage analysis and whole-exome sequencing. In CACNA1G, we identified a c.5144G>A mutation, causing an arginine-to-histidine (p.Arg1715His) change in the voltage sensor S4 segment of the T-type channel protein Cav3.1. Two out of 479 index subjects screened subsequently harbored the same mutation. We performed electrophysiological experiments in HEK293T cells to compare the properties of the p.Arg1715His and wild-type Cav3.1 channels. The current-voltage and the steady-state activation curves of the p.Arg1715His channel were shifted positively, whereas the inactivation curve had a higher slope factor. Computer modeling in deep cerebellar nuclei (DCN) neurons suggested that the mutation results in decreased neuronal excitability. Taken together, these data establish CACNA1G, which is highly expressed in the cerebellum, as a gene whose mutations can cause ADCA. This is consistent with the neuropathological examination, which showed severe Purkinje cell loss. Our study further extends our knowledge of the link between calcium channelopathies and CAs.
Published: 2015

33. Multifunctional Curcumin-Nanocarriers Based on Host-Guest Interactions for Alzheimer Disease Diagnostic

Author: Lazar, Adina N, Ramdani, Linda, Bourboulou, Romain, Belkouch, Mounir, Langui, Dominique, Jebors, Said, Tauran, Yannick, Parizot, Christophe, Suwinska, Kinga, Coleman, Anthony w., Duyckaerts, Charles, Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire des Multimatériaux et Interfaces (LMI), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Service d'Immunologie [CHU Pitié-Salpétrière], Polish Academy of Sciences (PAN), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], and Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP]
Subjects: [CHIM.COOR]Chemical Sciences/Coordination chemistry, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], [CHIM.MATE]Chemical Sciences/Material chemistry, [SDV.SP]Life Sciences [q-bio]/Pharmaceutical sciences, ComputingMilieux_MISCELLANEOUS
Abstract: International audience
Published: 2015

34. A mutation of spastin is responsible for swellings and impairment of transport in a region of axon characterized by changes in microtubule composition

Author: Jeremie Vitte, Anne Tarrade, Sabrina Courageot, Judith Melki, Etienne Mouisel, Delphine Charvin, Alain Thorel, Andrée Dierich, Nuria Fonknechten, Danielle Seilhean, Coralie Fassier, Natacha Roblot, Leticia Peris, Jean Jacques Hauw, Neurogenetique Moleculaire, Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), Organisation Fonctionnelle du Cytosquelette, Université Joseph Fourier - Grenoble 1 (UJF)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR27, Centre des Matériaux (MAT), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Centre National de la Recherche Scientifique (CNRS), Génomique métabolique (UMR 8030), Genoscope - Centre national de séquençage [Evry] (GENOSCOPE), Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université d'Évry-Val-d'Essonne (UEVE), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Institut de génétique et biologie moléculaire et cellulaire (IGBMC), Université Louis Pasteur - Strasbourg I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Collaboration, Centre des Matériaux (CDM), Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Andrieux, Annie
Subjects: Central Nervous System, Spastin, MESH: Base Sequence, Microtubules, MESH: Mice, Knockout, Mice, MESH: Protein Structure, Tertiary, 0302 clinical medicine, MESH: Behavior, Animal, MESH: Animals, Axon, Cells, Cultured, Genetics (clinical), MESH: Heterozygote, Adenosine Triphosphatases, Cerebral Cortex, Mice, Knockout, Motor Neurons, Genetics, 0303 health sciences, Behavior, Animal, MESH: Microtubules, Homozygote, Exons, General Medicine, Cell biology, medicine.anatomical_structure, MESH: Microscopy, Electron, Transmission, Microtubule-Associated Proteins, MESH: Motor Neurons, MESH: Homozygote, MESH: Cells, Cultured, Heterozygote, MESH: Axons, MESH: Mutation, Neurite, Microtubule-associated protein, MESH: Biological Transport, Blotting, Western, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, 03 medical and health sciences, Microscopy, Electron, Transmission, Microtubule, Neurites, [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology, MESH: Adenosine Triphosphatases, medicine, Animals, MESH: Blotting, Western, MESH: Central Nervous System, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Growth cone, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, MESH: Mice, Molecular Biology, 030304 developmental biology, Base Sequence, Biological Transport, MESH: Neurites, Axons, MESH: Cerebral Cortex, Protein Structure, Tertiary, MESH: Microtubule-Associated Proteins, MESH: Gene Deletion, Mutation, Axoplasmic transport, Neuron, MESH: Exons, Gene Deletion, 030217 neurology & neurosurgery
Abstract: International audience; Mutations of the spastin gene (Sp) are responsible for the most frequent autosomal dominant form of spastic paraplegia, a disease characterized by the degeneration of corticospinal tracts. We show that a deletion in the mouse Sp gene, generating a premature stop codon, is responsible for progressive axonal degeneration, restricted to the central nervous system, leading to a late and mild motor defect. The degenerative process is characterized by focal axonal swellings, associated with abnormal accumulation of organelles and cytoskeletal components. In culture, mutant cortical neurons showed normal viability and neurite density. However, they develop neurite swellings associated with focal impairment of retrograde transport. These defects occur near the growth cone, in a region characterized by the transition between stable microtubules rich in detyrosinated alpha-tubulin and dynamic microtubules composed almost exclusively of tyrosinated alpha-tubulin. Here, we show that the Sp mutation has a major impact on neurite maintenance and transport both in vivo and in vitro. These results highlight the link between spastin and microtubule dynamics in axons, but not in other neuronal compartments. In addition, it is the first description of a human neurodegenerative disease which involves this specialized region of the axon.
Published: 2006

35. Prognostic value of initial magnetic resonance imaging growth rates for World Health Organization grade II gliomas

Author: Luc Taillandier, Johan Pallud, Emmanuel Mandonnet, Rémy Guillevin, Damien Galanaud, Michèle Kujas, Laurent Capelle, Hugues Duffau, Service de Neurochirurgie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Neuroradiologie [CHU Pitié-Salpêtrière], Departement de neurologie, Hôpital Central, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Saidi, Vanessa, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Statistics as Topic, MESH: World Health Organization, MESH: Magnetic Resonance Imaging, MESH: Glioma, 0302 clinical medicine, MESH: Aged, MESH: Middle Aged, medicine.diagnostic_test, Brain Neoplasms, MESH: Follow-Up Studies, Glioma, Middle Aged, Magnetic Resonance Imaging, 3. Good health, Neurology, MESH: Survival Analysis, 030220 oncology & carcinogenesis, MESH: Brain Neoplasms, Disease Progression, MESH: Disease Progression, [SDV.IB]Life Sciences [q-bio]/Bioengineering, Female, MESH: Statistics, MESH: Ki-67 Antigen, Adult, Adolescent, World Health Organization, World health, Central nervous system disease, 03 medical and health sciences, medicine, Humans, Tumor growth, Inverse correlation, Survival analysis, Aged, Retrospective Studies, [SDV.IB] Life Sciences [q-bio]/Bioengineering, MESH: Adolescent, MESH: Humans, business.industry, Editorials, MESH: Adult, MESH: Retrospective Studies, Magnetic resonance imaging, Retrospective cohort study, medicine.disease, Survival Analysis, MESH: Male, Ki-67 Antigen, Neurology (clinical), Nuclear medicine, business, MESH: Female, 030217 neurology & neurosurgery, Follow-Up Studies
Abstract: A consecutive series of 143 unselected adult patients with histologically proved World Health Organization grade II gliomas was reviewed to assess the prognostic value of growth rates of mean tumor diameters on successive magnetic resonance images before treatment. There is an inverse correlation between growth rates and survival (p < 0.001; median survival at 5.16 years for a growth rate of 8mm/year or more; median survival >15.0 years for a growth rate
Published: 2006

36. Ultra performance liquid chromatography - mass spectrometry studies of formalin-induced alterations of human brain lipidome

Author: Ayciriex , Sophie, Gaudin , Mathieu, Panchal , Mai, Werner , Erwan, Brunelle , Alain, Touboul , David, Boursier-Neyret , Claire, Auzeil , Nicolas, Walther , Bernard, Duyckaerts , Charles, Laprévote , Olivier, Faculté de Pharmacie de Paris - Université Paris Descartes (UPD5 Pharmacie), Université Paris Descartes - Paris 5 (UPD5), Max Planck Institute of Molecular Cell Biology and Genetics (MPI-CBG), Max-Planck-Gesellschaft, Géosciences Marines (GM), Institut Français de Recherche pour l'Exploitation de la Mer (IFREMER), Institut de Chimie des Substances Naturelles (ICSN), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Etude du Métabolisme des Médicaments (LEMM), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire (EA 4463), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Faculté de Pharmacie de Paris (UPD5 Pharmacie), Unité de recherche Géosciences Marines (Ifremer) (GM), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Faculté de Pharmacie de Paris ( UPD5 Pharmacie ), Université Paris Descartes - Paris 5 ( UPD5 ), Max Planck Institute for Cell Biology and Genetics, Max-Planck-Institut, Institut des Sciences Analytiques ( ISA ), École normale supérieure - Lyon ( ENS Lyon ) -Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique ( CNRS ), Université Claude Bernard Lyon 1 ( UCBL ), Université de Lyon, Unité de recherche Géosciences Marines (Ifremer) ( GM ), Institut Français de Recherche pour l'Exploitation de la Mer ( IFREMER ), ICNS - Institut de Chimie des Substances naturelles, Laboratoire d'Etude du Métabolisme des Médicaments ( LEMM ), Service de Pharmacologie et Immunoanalyse ( SPI ), Département Médicaments et Technologies pour la Santé ( DMTS ), Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) ( DRF (CEA) ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Département Médicaments et Technologies pour la Santé ( DMTS ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay-Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Université Paris-Saclay, Institut de Chimie des Substances Naturelles ( ICSN ), Centre National de la Recherche Scientifique ( CNRS ), Laboratoire de Chimie et Toxicologie Analytique et Cellulaire ( EA 4463 ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), and CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], [CHIM.ORGA]Chemical Sciences/Organic chemistry, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [ SDV.BBM.BC ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], [ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [CHIM.ANAL]Chemical Sciences/Analytical chemistry, [ SDV.NEU.NB ] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [ CHIM.ANAL ] Chemical Sciences/Analytical chemistry, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], [ SDV.BIBS ] Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], ComputingMilieux_MISCELLANEOUS, [ SDV.BBM.BS ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM]
Abstract: International audience
Published: 2014

37. Inside Alzheimer brain with CLARITY: senile plaques, neurofibrillary tangles and axons in 3-D

Author: Ihsen Youssef, Amy M. Pooler, Charles Duyckaerts, Adina N. Lazar, Benoît Delatour, Quentin Laborde, Majid Amar, Marie-Claude Potier, David Godefroy, Kunie Ando, CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Institut de la Vision, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Différenciation et communication neuronale et neuroendocrine (DC2N), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Lipides et Neurodégénérescence dans la maladie d'Alzheimer (LIPIDOMIX), Institut National Polytechnique de Lorraine (INPL), Institute of Psychiatry, Psychology & Neuroscience, King's College London, King‘s College London, Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Godefroy, David, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Pathology, medicine.medical_specialty, Neurofilament, Databases, Factual, Intermediate Filaments, Clinical Neurology, Neuroimaging, Plaque, Amyloid, Pathology and Forensic Medicine, law.invention, 03 medical and health sciences, Cellular and Molecular Neuroscience, chemistry.chemical_compound, Imaging, Three-Dimensional, 0302 clinical medicine, Alzheimer Disease, Confocal microscopy, law, Correspondence, medicine, Humans, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Senile plaques, Paraformaldehyde, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Amyloid beta-Peptides, biology, Chemistry, Brain, Neurofibrillary Tangles, Sciences bio-médicales et agricoles, Primary and secondary antibodies, 3. Good health, Vibratome, Postmortem Changes, biology.protein, Immunohistochemistry, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Neurology (clinical), 030217 neurology & neurosurgery, Immunostaining
Abstract: Alzheimer’s disease (AD) is characterized by extracellular deposits of amyloid β (Aβ) peptide and intracellular tau aggregates. Examination of these lesions in post-mortem brain tissue routinely provides a two-dimensional picture of the pathology with a limited depth of field. Several tissue-clearing protocols have been recently published [1, 4–6, 8, 10, 11, 16]. We compared the quality of immunostaining on post-mortem human brain tissues using several clearing techniques including CLARITY [4, 5], Scale [8], SeeDB [9], and 3DISCO [6]. Results were best with CLARITY. In that method, acrylamide hydrogel links the protein of the tissue and maintains its structure. Removing the lipids makes the block transparent and facilitates antibody diffusion [4, 5]. We noticed that the results were improved if ScaleA2 [8] was used to mount the block after CLARITY. Formalin-fixed frontal cortex samples from two controls and five AD individuals (Braak VI and Thal 5) were obtained from the Brain Bank GIE NeuroCEB with legal consent. Brain samples were cut at a thickness of 500 μm with a vibratome and were processed by the CLARITY technique [5]. Embedded in an acrylamide hydrogel constituted of 4 % paraformaldehyde (PFA), 4 % acrylamide, 0.25 % temperature-triggering initiator VA-044, PBS, the tissues were passively clarified at 37 °C for 2 weeks in the clearing solution (200 mM boric acid, 4 % w/v SDS, pH 8.5). The blocks were immunostained with a rabbit polyclonal anti-tau B19 antibody [3] and a mouse monoclonal anti-Aβ 4G8 antibody (Covance). Alexa Fluor® 488 goat anti-rabbit and Alexa Fluor® 568 goat anti-mouse antibodies (Life technologies) were used as secondary antibodies. For Aβ and neurofilament double immunohistochemistry, the tissues were first incubated with mouse monoclonal anti-neurofilament antibody (M0762 Dako) and then with Alexa Fluor® 568 goat anti-mouse antibody. After a blocking stage (10 % normal mouse serum), the tissues were incubated with biotin-labelled 4G8 anti-Aβ antibody (Covance), revealed with DyLight 488-labelled streptavidin (KPL, Eurobio, France). Triple staining (Aβ, tau and neurofilament) was also performed: the block was incubated with anti-tau B19 and anti-neurofilament M0762 antibodies revealed with the secondary Alexa Fluor® 488 goat anti-rabbit and Alexa Fluor® 568 goat anti-mouse antibodies. The third antibody was a biotin-labelled anti-Aβ 4G8 antibody (Covance) revealed with streptavidin-Alexa 405 (Life technology). The mounting protocol was modified from the original method: we added a fixation step (4 % PFA in PBS for 15 min) at the end of the procedure to improve the stability of the immunostaining, and an incubation step (0.2 M glycine for 15 min) to quench autofluorescence. We used ScaleA2 solution as mounting medium [8], instead of 80 % glycerol or FocusClear described in the original method [5]. ScaleA2 increased the transparency of the tissue compared to 80 % glycerol, lowered the cost of the experiment compared to FocusClear and shortened incubation time (overnight compared to 2 days). The immunolabellings were analysed with an upright confocal microscope (Olympus Fluoview Fv1000). The Z-stack images were re-constructed using Imaris software (Bitplane). The volume of the “clarified” block was increased by approximately 40 % after passive removal of the lipids. While 80 % glycerol or FocusClear restored the volume in the original CLARITY technique, ScaleA2 further increased it but kept the morphological quality of the technique. The combination of CLARITY and ScaleA2 is not appropriate for stereological measures because of the volume expansion. Despite the increase in volume, the axons (shown by neurofilament immunostaining) remained continuous (Supplementary 10.1007/s00401-014-1322-y). The clarified tissues were fully transparent. The video, obtained with confocal microscopy, provides a 3-D view of the lesions revealed by Aβ and tau immunohistochemistry (10.1007/s00401-014-1322-y). Amyloid deposits appeared to have diverse 3-D structure in AD brains: some deposits were dense and focal; some diffuse deposits appeared hollow (10.1007/s00401-014-1322-y). Accumulation of Aβ was regularly spaced in clumps throughout the cortex (10.1007/s00401-014-1322-y). Tau accumulated in segmented and discontinuous neuritic processes. Many dystrophic neurites were associated with dense, focal, presumably “mature” Aβ focal deposits [2]. Plaque-induced distorted neurites have been previously reported by in vivo observation in AD transgenic animal [7, 12, 13, 15] and in the affected areas of post-mortem human AD brains [10, 14]. Our video of Aβ and neurofilament double immunostaining showed the persistence of a large number of axons, one of them (traced in yellow) deflected by the focal deposits (10.1007/s00401-014-1322-y). Finally, a triple immunostaining for Aβ (blue), tau (green) and neurofilament (red) showed that the tangle bearing neuron that we identified had no visible axonal projection (10.1007/s00401-014-1322-y). The region of the Aβ focal deposit contained few axons. The Aβ immunoreactivity (revealed with an avidin biotin amplification step) was excellent through the whole thickness of the block. Neurofilament and tau immunoreactivities (revealed with no amplification step) were stronger in a 150-µm-thick layer at the top of the block. The transparency of the block was, however, homogeneous. The 150-µm-thick layer of high immunoreactivity was detected at the top and at the bottom of the block: it was not related to a defect in the penetration of the laser beam during the imaging process but to better antibody penetration near the surface. Longer incubation time, higher concentration of detergent in the buffer and various amplification systems will be tested in the future to improve the homogeneity of the signal throughout the thickness of the sample. These first results uncover the 3-D architecture of AD lesions and demonstrate the utility of the CLARITY technique in studying the distribution of AD pathology in 3-D, even in post-mortem human tissue.
Published: 2014

38. Perspective on future role of biological markers in clinical therapy trials of Alzheimer's disease: A long-range point of view beyond 2020

Author: Lars Bertram, Hovagim Bakardjian, Stéphane Epelbaum, Alexander Drzezga, Paul S. Aisen, Robert Nisticò, Alexis Brice, Kaj Blennow, Charles Duyckaerts, Karl Broich, Stefan J. Teipel, Stéphane Lehéricy, Francesco Giuseppe Garaci, Bruno Dubois, Simone Lista, Zaven S. Khachaturian, Olivier Colliot, Harald Hampel, Henrik Zetterberg, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut de la Mémoire et de la Maladie d'Alzheimer [CHU Pitié-Salpétriêre] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Department of Psychosomatic Medicine [Rostock], University of Rostock, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS San Raffaele Pisana), Department of Physiology and Pharmacology [Rome], Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Department of Psychiatry and Neurochemistry [Goteborg], Institute of Neuroscience and Physiology [Göteborg]-Sahlgrenska Academy at University of Gothenburg [Göteborg], Department of Vertebrate Genomics [Berlin], Max-Planck-Institut für Molekulare Genetik (MPIMG), Max-Planck-Gesellschaft-Max-Planck-Gesellschaft, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Department of Nuclear Medicine [Cologne], University Hospital of Cologne [Cologne], Algorithms, models and methods for images and signals of the human brain (ARAMIS), Inria Paris-Rocquencourt, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Federal Institute of Drugs and Medical Devices [Bonn], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Prevent Alzheimer’s Disease 2020 [Rockville] (PAD 2020), Department of Neurosciences [Univ California San Diego] (Neuro - UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut de la Mémoire et de la Maladie d'Alzheimer [Paris] (IM2A), Université Pierre et Marie Curie - Paris 6 (UPMC), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Department of Neurosciences [San Diego], University of California-University of California, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: CSF/blood biomarkers, Psychological intervention, Disease, Bioinformatics, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Clinical trials, alzheimer's disease, clinical trials, csf/blood biomarkers, pet imaging markers, structural/functional mri markers, Alzheimer Disease, Structural/functional MRI markers, Medicine, Humans, ddc:610, 030304 developmental biology, Pharmacology, 0303 health sciences, Alzheimer's disease, PET imaging markers, Biological Markers, Clinical Trials as Topic, Operationalization, Conceptualization, therapy [Alzheimer Disease], business.industry, Perspective (graphical), Settore BIO/14, medicine.disease, 3. Good health, Clinical trial, Clinical therapy, business, Neuroscience, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, 030217 neurology & neurosurgery, metabolism [Alzheimer Disease], Biomarkers, metabolism [Biomarkers]
Abstract: International audience; Recent advances in understanding the molecular mechanisms underlying various paths toward the pathogenesis of Alzheimer's disease (AD) has begun to provide new insight for interventions to modify disease progression. The evolving knowledge gained from multidisciplinary basic research has begun to identify new concepts for treatments and distinct classes of therapeutic targets; as well as putative disease-modifying compounds that are now being tested in clinical trials. There is a mounting consensus that such disease modifying compounds and/or interventions are more likely to be effectively administered as early as possible in the cascade of pathogenic processes preceding and underlying the clinical expression of AD. The budding sentiment is that "treatments" need to be applied before various molecular mechanisms converge into an irreversible pathway leading to morphological, metabolic and functional alterations that characterize the pathophysiology of AD. In light of this, biological indicators of pathophysiological mechanisms are desired to chart and detect AD throughout the asymptomatic early molecular stages into the prodromal and early dementia phase. A major conceptual development in the clinical AD research field was the recent proposal of new diagnostic criteria, which specifically incorporate the use of biomarkers as defining criteria for preclinical stages of AD. This paradigm shift in AD definition, conceptualization, operationalization, detection and diagnosis represents novel fundamental opportunities for the modification of interventional trial designs. This perspective summarizes not only present knowledge regarding biological markers but also unresolved questions on the status of surrogate indicators for detection of the disease in asymptomatic people and diagnosis of AD.
Published: 2014

39. PDK1 decreases TACE-mediated alpha-secretase activity and promotes disease progression in prion and Alzheimer's diseases

Author: Aurélie Alleaume-Butaux, Samia Hannaoui, Yannick Bailly, Caroline Dakowski, Audrey Ragagnin, Mathéa Pietri, Julia Hernandez-Rapp, Jean-Marie Launay, Jean-Michel Peyrin, Stéphane Haïk, Odile Kellermann, Benoit Schneider, Sophie Mouillet-Richard, Neuroscience Paris Seine (NPS), Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), French Agence Nationale pour la Recherche (PrionsSensiTNF) [1312 01], INSERM, Domaine d'Interet Majeur - Maladies Infectieuses - Region Ile-de-France, Toxicité environnementale, cibles thérapeutiques, signalisation cellulaire (T3S - UMR_S 1124), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Neurosciences Cellulaires et Intégratives (INCI), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche des Cordeliers (CRC (UMR_S_1138 / U1138)), École pratique des hautes études (EPHE)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université de Franche-Comté (UFC), Adaptation Biologique et Vieillissement = Biological Adaptation and Ageing (B2A), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de biochimie INSERM UMR-S942, Hôpital Lariboisière-APHP, Faculté de Pharmacie, Service de Biochimie et Biologie Moléculaire, hôpital Lariboisière, AP-HP, EA 3621, Université Paris Descartes - Paris 5 (UPD5), Laboratoire de psychologie de l'interaction et des relations intersubjectives (INTERPSY), Université de Lorraine (UL), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neurobiologie des processus adaptatifs (NPA), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), Pharmacologie, toxicologie et signalisation cellulaire (U747), Université Paris Descartes - Paris 5 (UPD5)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), École pratique des hautes études (EPHE), CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Neurosciences Paris Seine (NPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)
Subjects: animal diseases, Caveolin 1, Prion Diseases, Amyloid beta-Protein Precursor, Mice, 0302 clinical medicine, Amyloid precursor protein, ADAM17 Protein, Phosphorylation, RNA, Small Interfering, Internalization, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, media_common, 0303 health sciences, biology, Brain, General Medicine, 3. Good health, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM], Receptors, Tumor Necrosis Factor, Type I, Disease Progression, RNA Interference, Tumor necrosis factor alpha, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Alzheimer's disease, Cell Survival, Prions, media_common.quotation_subject, Mice, Transgenic, Protein Serine-Threonine Kinases, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Alzheimer Disease, medicine, Animals, Humans, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], 030304 developmental biology, Amyloid beta-Peptides, Tumor Necrosis Factor-alpha, Neurotoxicity, Pyruvate Dehydrogenase Acetyl-Transferring Kinase, medicine.disease, nervous system diseases, Mice, Inbred C57BL, ADAM Proteins, Immunology, biology.protein, Cancer research, Amyloid Precursor Protein Secretases, Amyloid precursor protein secretase, 030217 neurology & neurosurgery
Abstract: International audience; alpha-secretase-mediated cleavage of amyloid precursor protein (APP) precludes formation of neurotoxic amyloid-beta (A beta) peptides, and alpha-cleavage of cellular prion protein (Pr-Pc) prevents its conversion into misfolded, pathogenic prions (PrPSc). The mechanisms leading to decreased alpha-secretase activity in Alzheimer's and prion disease remain unclear. Here, we find that tumor necrosis factor-alpha-converting enzyme (TACE)-mediated alpha-secretase activity is impaired at the surface of neurons infected with PrPSc or isolated from APP-transgenic mice with amyloid pathology. 3-phosphoinositide-dependent kinase-1 (PDK1) activity is increased in neurons infected with prions or affected by A beta deposition and in the brains of individuals with Alzheimer's disease. PDK1 induces phosphorylation and caveolin-l-mediated internalization of TACE. This dysregulation of TACE increases PrPSc and A beta accumulation and reduces shedding of TNF-alpha receptor type 1 (TNFR1). Inhibition of PDK1 promotes localization of TACE to the plasma membrane, restores TACE-dependent alpha-secretase activity and cleavage of APP, PrPC and TNFR1, and attenuates PrPSc- and A beta-induced neurotoxicity. In mice, inhibition or siRNA-mediated silencing of PDK1 extends survival and reduces motor impairment following PrPSc infection and in APP-transgenic mice reduces Alzheimer's disease-like pathology and memory impairment.
Published: 2013

40. Mutations in SQSTM1 encoding p62 in amyotrophic lateral sclerosis: genetics and neuropathology

Author: Guillaume Bataillon, Vincent Meininger, Danielle Seilhean, Takahiro Takeda, Séverine Boillée, Elisa Teyssou, Brahima Doukouré, Véronique Sazdovitch, Vincent Lebon, Cécile Cazeneuve, François Salachas, Stéphanie Millecamps, Eric LeGuern, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and MILLECAMPS, Stéphanie
Subjects: Adult, Male, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Heterozygote, Neuropathology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, Pathology and Forensic Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Exon, 0302 clinical medicine, Sequestosome 1, Sequestosome-1 Protein, Genetic predisposition, medicine, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Missense mutation, Humans, Amyotrophic lateral sclerosis, education, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Adaptor Proteins, Signal Transducing, Aged, Genetics, Aged, 80 and over, 0303 health sciences, education.field_of_study, Ubiquitin, Amyotrophic Lateral Sclerosis, Intron, Brain, Heterozygote advantage, Middle Aged, medicine.disease, 3. Good health, DNA-Binding Proteins, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: Mutations in SQSTM1 encoding the sequestosome 1/p62 protein have recently been identified in familial and sporadic cases of amyotrophic lateral sclerosis (ALS). p62 is a component of the ubiquitin inclusions detected in degenerating neurons in ALS patients. We sequenced SQSTM1 in 90 French patients with familial ALS (FALS) and 74 autopsied ALS cases with sporadic ALS (SALS). We identified, at the heterozygote state, one missense c.1175C>T, p.Pro392Leu (exon 8) in one of our FALS and one substitution in intron 7 (the c.1165+1G>A, previously called IVS7+1 G-A, A390X) affecting the exon 7 splicing site in one SALS. These mutations that are located in the ubiquitin-associated domain (UBA domain) of the p62 protein have already been described in Paget’s disease and ALS patients carrying these mutations had both concomitant Paget’s disease. However, we also identified two novel missense mutations in two SALS: the c.259A>G, p.Met87Val in exon 2 and the c.304A>G, p.Lys102Glu in exon 3. These mutations that were not detected in 360 control subjects are possibly pathogenic. Neuropathology analysis of three patients carrying SQSTM1 variants revealed the presence of large round p62 inclusions in motor neurons, and immunoblot analysis showed an increased p62 and TDP-43 protein levels in the spinal cord. Our results confirm that SQSTM1 gene mutations could be the cause or genetic susceptibility factor of ALS in some patients.
Published: 2013

41. Expression of follicle-stimulating hormone receptor by the vascular endothelium in tumor metastases

Author: Aurelian Radu, Nicolae Ghinea, Philippe Camparo, Gaëlle Fromont, Martine Antoine, François Planeix, Julie Gonin, Christophe Pichon, Virginie Desestret, Michel Huerre, Ahsan Siraj, Marc Sanson, BMC, Ed., Département de Recherche Translationnelle, Institut Curie [Paris], Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service d'Anatomie et cytologie pathologiques [CHU Tenon], CHU Tenon [AP-HP], Service d'Anatomie et de Cytologie Pathologiques [Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Histotechnologie et Pathologie, Institut Pasteur [Paris] (IP), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Centre de pathologie Amiens, Centre de pathologie Amiens - Picardie, Icahn School of Medicine at Mount Sinai [New York] (MSSM), Département de recherche translationnelle, Institut Curie, Laboratoire de Neuropathologie Raymond Escourolle, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Service d'anatomie pathologique [CHU Tenon], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Tenon [APHP], Institut Pasteur [Paris], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Tenon [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)
Subjects: Male, Leiomyosarcoma, Cancer Research, Pathology, Lung Neoplasms, Endothelial cells, Estrogen receptor, Metastasis, Prostate cancer, 0302 clinical medicine, Breast cancer, Neoplasms, Medicine, Neoplasm Metastasis, Lymph node, 0303 health sciences, Tumor blood vessels, Kidney cancer, Middle Aged, Kidney Neoplasms, Colon cancer, medicine.anatomical_structure, Oncology, 030220 oncology & carcinogenesis, Lymphatic Metastasis, Colonic Neoplasms, Uterine Neoplasms, Receptors, FSH, Female, Lung cancer, Research Article, Adult, medicine.medical_specialty, endocrine system, Endothelium, [SDV.CAN]Life Sciences [q-bio]/Cancer, Breast Neoplasms, 03 medical and health sciences, Young Adult, [SDV.CAN] Life Sciences [q-bio]/Cancer, Genetics, Humans, 030304 developmental biology, Aged, Follicle-stimulating hormone receptor, business.industry, Cancer, Prostatic Neoplasms, medicine.disease, Microvessels, Endothelium, Vascular, business
Abstract: Background The Follicle Stimulating Hormone receptor (FSHR) is expressed by the vascular endothelium in a wide range of human tumors. It was not determined however if FSHR is present in metastases which are responsible for the terminal illness. Methods We used immunohistochemistry based on a highly FSHR-specific monoclonal antibody to detect FSHR in cancer metastases from 6 major tumor types (lung, breast, prostate, colon, kidney, and leiomyosarcoma ) to 6 frequent locations (bone, liver, lymph node, brain, lung, and pleura) of 209 patients. Results In 166 patients examined (79%), FSHR was expressed by blood vessels associated with metastatic tissue. FSHR-positive vessels were present in the interior of the tumors and some few millimeters outside, in the normally appearing tissue. In the interior of the metastases, the density of the FSHR-positive vessels was constant up to 7 mm, the maximum depth available in the analyzed sections. No significant differences were noticed between the density of FSHR-positive vessels inside vs. outside tumors for metastases from lung, breast, colon, and kidney cancers. In contrast, for prostate cancer metastases, the density of FSHR-positive vessels was about 3-fold higher at the exterior of the tumor compared to the interior. Among brain metastases, the density of FSHR-positive vessels was highest in lung and kidney cancer, and lowest in prostate and colon cancer. In metastases of breast cancer to the lung pleura, the percentage of blood vessels expressing FSHR was positively correlated with the progesterone receptor level, but not with either HER-2 or estrogen receptors. In normal tissues corresponding to the host organs for the analyzed metastases, obtained from patients not known to have cancer, FSHR staining was absent, with the exception of approx. 1% of the vessels in non tumoral temporal lobe epilepsy samples. Conclusion FSHR is expressed by the endothelium of blood vessels in the majority of metastatic tumors.
Published: 2012

42. Substitutions at residue 211 in the prion protein drive a switch between CJD and GSS syndrome, a new mechanism governing inherited neurodegenerative disorders

Author: Etienne Levavasseur, Jean-Louis Laplanche, Philippe Derreumaux, Human Rezaei, Céline Chapuis, Nicolas Privat, Katell Peoc'h, M. Borg, Isabelle Laffont-Proust, Pierre Bedoucha, Yassmine Chebaro, Annie Laquerrière, Stéphane Haïk, Jean-Jacques Hauw, Alfonso De Simone, Jean-Louis Kemeny, Jean-Philippe Brandel, Emilien Delmont, Service de Biochimie et de Biologie moléculaire, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Nice, Centre Hospitalier Universitaire de Nice (CHU Nice), Laboratoire de biochimie théorique [Paris] (LBT (UPR_9080)), Institut de biologie physico-chimique (IBPC (FR_550)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement (Néovasc), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de Neurologie, Hôpital Pasteur [Nice] (CHU)-Centre Hospitalier Universitaire de Nice (CHU Nice), Unité de recherche Virologie et Immunologie Moléculaires (VIM (UR 0892)), Institut National de la Recherche Agronomique (INRA), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Institut National de la Sante et de la Recherche Medicale' (INSERM), 'Assistance Publique - Hopitaux de Paris (AP-HP), 'Fondation Thierry et Annick Desmarest - Institut de France', 'Institut National de Veille Sanitaire' (InVS, CNR-TNC), Hénin, Jérôme, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC (FR_550)), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Normandie Université (NU)-Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Peoc'H, K., Levavasseur, E., Delmont, E., De simone, A., Laffont-proust, I., Privat, N., Chebaro, Y., Chapuis, C., Bedoucha, P., Brandel, J., Laquerriere, A., Kemeny, J., Hauw, J., Borg, M., Rezaei, H., Derreumaux, P., Laplanche, J., Haik, S., Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut de biologie physico-chimique (IBPC), Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Diderot - Paris 7 (UPD7), Service d'Anatomie et Cytologie Pathologique [Rouen], Institute for Research and Innovation in Biomedicine (IRIB), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Unité de recherche Virologie et Immunologie Moléculaires (VIM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Descartes - Paris 5 ( UPD5 ) -Faculté de Pharmacie-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP], Laboratoire de biochimie théorique [Paris] ( LBT ), Université Paris Diderot - Paris 7 ( UPD7 ) -Centre National de la Recherche Scientifique ( CNRS ), Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), CHU Rouen-Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ), Endothélium microcirculatoire cérébral et lésions du système nerveux central au cours du développement ( Néovasc ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institute for Research and Innovation in Biomedicine ( IRIB ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Pasteur [Nice] ( CHU ) -CHU Nice, Unité de recherche Virologie et Immunologie Moléculaires ( VIM ), Institut National de la Recherche Agronomique ( INRA ), and CHU Pitié-Salpêtrière [APHP]-Assistance publique - Hôpitaux de Paris (AP-HP)-Université Pierre et Marie Curie - Paris 6 ( UPMC )
Subjects: Models, Molecular, [ SDV.BBM.BP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Prions, Protein Conformation, animal diseases, Mutant, PrPSc Proteins, [SDV.BBM.BP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Plaque, Amyloid, Biology, Molecular Dynamics Simulation, medicine.disease_cause, Creutzfeldt-Jakob Syndrome, 03 medical and health sciences, 0302 clinical medicine, Protein structure, Genetics, medicine, Gerstmann-Straussler-Scheinker Disease, Humans, Senile plaques, Cloning, Molecular, Phosphorylation, Molecular Biology, Gene, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, Mutation, General Medicine, Phenotype, 3. Good health, nervous system diseases, [SDV.BBM.BP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biophysics, Gliosis, Amino Acid Substitution, medicine.symptom, 030217 neurology & neurosurgery
Abstract: Human prion diseases are a heterogeneous group of fatal neurodegenerative disorders, characterized by the deposition of the partially protease-resistant prion protein (PrPres), astrocytosis, neuronal loss and spongiform change in the brain. Among inherited forms that represent 15% of patients, different phenotypes have been described depending on the variations detected at different positions within the prion protein gene. Here, we report a new mechanism governing the phenotypic variability of inherited prion diseases. First, we observed that the substitution at residue 211 with either Gln or Asp leads to distinct disorders at the clinical, neuropathological and biochemical levels (Creutzfeldt-Jakob disease or Gerstmann-Sträussler-Scheinker syndrome with abundant amyloid plaques and tau neurofibrillar pathology). Then, using molecular dynamics simulations and biophysical characterization of mutant proteins and an in vitro model of PrP conversion, we found evidence that each substitution impacts differently the stability of PrP and its propensity to produce different protease resistant fragments that may contribute to the phenotypical switch. Thus, subtle differences in the PrP primary structure and stability are sufficient to control amyloid plaques formation and tau abnormal phosphorylation and fibrillation. This mechanism is unique among neurodegenerative disorders and is consistent with the prion hypothesis that proposes a conformational change as the key pathological event in prion disorders. © The Author 2012. Published by Oxford University Press.
Published: 2012

43. Muscle gene expression is a marker of amyotrophic lateral sclerosis severity

Author: Philippe Demougin, Marc de Tapia, Luc Dupuis, Timothée Lenglet, Odile Dubourg, Jean-Christophe Corvol, François Salachas, Vincent Meininger, Michael Primig, Jean-Philippe Loeffler, Pierre-François Pradat, Gaëlle Bruneteau, Jose-Luis Gonzalez de Aguilar, Franck Di Scala, Lucette Lacomblez, Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de signalisation moléculaire et neurodégénerescence, Université Louis Pasteur - Strasbourg I-IFR37-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Biozentrum [Basel, Suisse], University of Basel (Unibas), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Biozentrum
Subjects: Male, Pathology, MESH: Genetic Markers, Manual Muscle Testing, 0302 clinical medicine, Degenerative disease, Myocyte, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, MESH: Aged, 0303 health sciences, MESH: Middle Aged, Deltoid Muscle, Middle Aged, MESH: Gene Expression Regulation, MESH: Case-Control Studies, Muscle atrophy, Muscular Atrophy, medicine.anatomical_structure, Neurology, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], medicine.symptom, Adult, Genetic Markers, medicine.medical_specialty, Adolescent, Biology, MESH: Deltoid Muscle, 03 medical and health sciences, MESH: Gene Expression Profiling, Atrophy, Deltoid muscle, medicine, Humans, 030304 developmental biology, Aged, MESH: Adolescent, MESH: Humans, Gene Expression Profiling, Amyotrophic Lateral Sclerosis, MESH: Muscular Atrophy, Skeletal muscle, MESH: Adult, medicine.disease, MESH: Male, Gene Expression Regulation, Case-Control Studies, Neurology (clinical), MESH: Female, 030217 neurology & neurosurgery
Abstract: Background: Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset degenerative disease characterized by the loss of upper and lower motor neurons leading to progressive muscle atrophy and paralysis. The lack of molecular markers of the progression of disease is detrimental to clinical practice and therapeutic trials. Objective: This study was designed to identify gene expression changes in skeletal muscle that could reliably define the degree of disease severity. Methods: Gene expression profiles were obtained from the deltoid muscles of ALS patients and healthy subjects. Changes in differentially expressed genes were compared to the status of deltoid muscle disability, as determined by manual muscle testing, electrophysiology and the degree of myofiber atrophy. Functionally related genes were grouped by annotation analysis, and deltoid muscle injury was predicted using binary tree classifiers. Results: Two sets of 25 and 70 transcripts appeared differentially regulated exclusively in early and advanced states of deltoid muscle impairment, respectively. The expression of another set of 198 transcripts correlated with a composite score of muscle injury combining manual muscle testing and histological examination. From the totality of these expression changes, 155 transcripts distinguished advanced from early deltoid muscle impairment with 80% sensitivity and 100% specificity. Nine of these transcripts, known also to be regulated in ALS mouse and surgically denervated muscle, predicted the advanced disease status with 100% sensitivity and specificity. Conclusion: We provide robust gene expression changes that can be of practical use when monitoring ALS status and the effects of disease-modifying drugs.
Published: 2012

44. Phenotype difference between ALS patients with expanded repeats in C9ORF72 and patients with mutations in other ALS-related genes

Author: François Salachas, Cécile Cazeneuve, Véronique Danel-Brunaud, Nadine Le Forestier, Isabelle Le Ber, Vincent Meininger, Gaëlle Bruneteau, Marine Giraudeau, Philippe Corcia, Eric LeGuern, Séverine Boillée, Elisa Teyssou, Lucette Lacomblez, Danielle Seilhean, Alexis Brice, Pierre-François Pradat, William Camu, Nadia Vandenberghe, Carine Moigneu, Stéphanie Millecamps, MILLECAMPS, Stéphanie, Institut du Cerveau = Paris Brain Institute (ICM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Assistance publique-Hôpitaux de Paris - Espace éthique (AP-HP Espace éthique), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1)
Subjects: Adult, Male, Oncology, medicine.medical_specialty, SOD1, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, TARDBP, Young Adult, 03 medical and health sciences, Superoxide Dismutase-1, 0302 clinical medicine, C9orf72, Internal medicine, Genetics, medicine, Humans, Amyotrophic lateral sclerosis, Genetic Association Studies, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, Aged, 80 and over, 0303 health sciences, DNA Repeat Expansion, C9orf72 Protein, Superoxide Dismutase, Amyotrophic Lateral Sclerosis, Age Factors, Proteins, Middle Aged, medicine.disease, DNA-Binding Proteins, Phenotype, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, RNA-Binding Protein FUS, Female, Age of onset, Trinucleotide repeat expansion, Motor neurone disease, 030217 neurology & neurosurgery, Frontotemporal dementia
Abstract: Background Expanded GGGGCC hexanucleotide repeats in the promoter of the C9ORF72 gene have recently been identified in frontotemporal dementia (FTD), Amyotrophic Lateral Sclerosis (ALS) and ALS-FTD and appear as the most common genetic cause of familial (FALS) and sporadic (SALS) forms of ALS. Methods We searched for the C9ORF72 repeat expansion in 950 French ALS patients (225 FALS and 725 SALS) and 580 control subjects and performed genotype-phenotype correlations. Results The repeat expansion was present in 46% of FALS, 8% of SALS and 0% of controls. Phenotype comparisons were made between FALS patients with expanded C9ORF72 repeats and patients carrying another ALS-related gene ( SOD1, TARDBP, FUS ) or a yet unidentified genetic defect. SALS patients with and without C9ORF72 repeat expansions were also compared. The C9ORF72 group presented more frequent bulbar onset both in FALS (p
Published: 2012

45. Neuropathology of sleep disorders: a review

Author: Chantal Hausser-Hauw, Dominique Hasboun, Danielle Seilhean, Jean-Jacques Hauw, Umberto De Girolami, Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Cortex et Epilepsie [Paris], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), The Mediterranean Institute of Neurobiology, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], and Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Sleep Wake Disorders, Pediatrics, medicine.medical_specialty, Hypothalamus, Excessive daytime sleepiness, Sleep, REM, Neuropathology, Insomnia, Fatal Familial, Nervous System, Pathology and Forensic Medicine, Progressive supranuclear palsy, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Biological Clocks, medicine, Insomnia, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Wakefulness, Psychiatry, 030304 developmental biology, Fatal familial insomnia, 0303 health sciences, Sleep disorder, Orexins, Lewy body, Neuropeptides, Intracellular Signaling Peptides and Proteins, Brain, Neurodegenerative Diseases, General Medicine, medicine.disease, 3. Good health, Neurology, Neurology (clinical), Sleep Stages, medicine.symptom, Psychology, Sleep, 030217 neurology & neurosurgery, Narcolepsy
Abstract: International audience; Sleep disorders are important manifestations of neurodegenerativediseases and sometimes are clinically evident well before the onset of other neurological manifestations. This review addresses theneuroanatomical basis and the mechanisms of sleep regulation in humans in relation to the neuropathology of entities associated with sleep disturbances in selected diseases, including Alzheimer disease, progressive supranuclear palsy, Lewy body disorders, multiple-system atrophy, and fatal familial insomnia. This includes abnormalities of circadian rhythm, insomnia, narcolepsy, rapid eye movements sleep behavior disorders, and excessive daytime sleepiness.
Published: 2011

46. SOD1, ANG, VAPB, TARDBP, and FUS mutations in familial amyotrophic lateral sclerosis: genotype-phenotype correlations

Author: Véronique Danel-Brunaud, Nadine Le Forestier, Nadia Vandenberghe, Stéphanie Millecamps, Agnès Camuzat, Gaëlle Bruneteau, Didier Hannequin, Isabelle Le Ber, Philippe Couratier, François Salachas, Alexis Brice, Paul H. Gordon, Vincent Meininger, Guy A. Rouleau, Bernard Bricka, Christel Thauvin-Robinet, Nathalie Guy, William Camu, Philippe Corcia, Eric LeGuern, Danielle Seilhean, Lucette Lacomblez, Odile Russaouen, Pierre-François Pradat, Cécile Cazeneuve, Lena Guillot-Noel, Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Fédération des Maladies du Système Nerveux, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), Service de neurologie et pathologie du mouvement, Hôpital Roger Salengro [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Centre de compétence de la Sclérose Latérale Amyotrophique [CHU Clermont-Ferrand] (SLA), CHU Gabriel Montpied [Clermont-Ferrand], CHU Clermont-Ferrand-CHU Clermont-Ferrand, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Neuroépidémiologie Tropicale et Comparée (NETEC), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM), Centre référent Sclérose Latérale Amyotrophique et autres maladies du motoneurone [CHU Limoges] (SLA CHU Limoges), CHU Limoges, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Neuropathologie Raymond Escourolle, Centre de compétence de la Sclérose Latérale Amyotrophique [CHRU Tours] (SLA CHRU Tours), Centre Hospitalier Régional Universitaire de Tours (CHRU TOURS), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Center of Excellence in Neuromics, Antenne ORL, Hôpital Henri Mondor-Hôpital Albert Chenevier-Groupe Hospitalier Universitaire Sud, Centre SLA, Hospices Civils de Lyon (HCL)-Hôpital neurologique et neurochirurgical Pierre Wertheimer [CHU - HCL], Hôpital Roger Salengro-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Neuro-Dol (Neuro-Dol), Université d'Auvergne - Clermont-Ferrand I (UdA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Center of Excellence in Neuromics, University of Montreal, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro, Service d'anatomie pathologique neurologique [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Grelier, Elisabeth, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Hôpital Roger Salengro [Lille]
Subjects: Male, MESH: Vesicular Transport Proteins, MESH: Ribonuclease, Pancreatic, Vesicular Transport Proteins, medicine.disease_cause, 0302 clinical medicine, MESH: Aged, 80 and over, Genotype, Missense mutation, Molecular genetics, Age of Onset, Amyotrophic lateral sclerosis, Genetics (clinical), MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase, MESH: Genetic Association Studies, Aged, 80 and over, Genetics, MESH: Aged, 0303 health sciences, Mutation, MESH: Middle Aged, MESH: RNA-Binding Protein FUS, Middle Aged, VAPB, Neuromuscular disease, 3. Good health, DNA-Binding Proteins, MESH: Longevity, Female, Adult, medicine.medical_specialty, MESH: Mutation, MESH: Age of Onset, Longevity, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, Biology, TARDBP, 03 medical and health sciences, Age Distribution, Motor neurone disease, medicine, Humans, Family, Clinical genetics, MESH: Age Distribution, MESH: Family, Genetic Association Studies, Aged, 030304 developmental biology, MESH: Humans, Superoxide Dismutase, [SCCO.NEUR]Cognitive science/Neuroscience, Amyotrophic Lateral Sclerosis, [SCCO.NEUR] Cognitive science/Neuroscience, MESH: Adult, Ribonuclease, Pancreatic, medicine.disease, MESH: Male, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, Clinical genetics, Molecular genetics, Motor neurone disease, Neuromuscular disease, RNA-Binding Protein FUS, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Age of onset, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: International audience; BACKGROUND: Mutations in SOD1, ANG, VAPB, TARDBP and FUS genes have been identified in amyotrophic lateral sclerosis (ALS). METHODS: The relative contributions of the different mutations to ALS were estimated by systematically screening a cohort of 162 families enrolled in France and 500 controls (1000 chromosomes) using molecular analysis techniques and performing phenotype-genotype correlations. RESULTS: 31 pathogenic missense mutations were found in 36 patients (20 SOD1, 1 ANG, 1 VAPB, 7 TARDBP and 7 FUS). Surprisingly two FUS mutation carriers also harboured ANG variants. One family of Japanese origin with the P56S VAPB mutation was identified. Seven novel mutations (three in SOD1, two in TARDBP, two in FUS) were found. None of them was detected in controls. Segregation of detected mutations with the disease was confirmed in 11 families including five pedigrees carrying the novel mutations. Clinical comparison of SOD1, TARDBP, FUS and other familial ALS patients (with no mutation in the screened genes) revealed differences in site of onset (predominantly lower limbs for SOD1 and upper limbs for TARDBP mutations), age of onset (younger with FUS mutations), and in lifespan (shorter for FUS carriers). One third of SOD1 patients survived more than 7 years: these patients had earlier disease onset than those presenting with a more typical course. Differences were also observed among FUS mutations, with the R521H FUS mutation being associated with longer disease duration. CONCLUSIONS: This study identifies new genetic associations with ALS and provides phenotype-genotype correlations with both previously reported and novel mutations.
Published: 2010

47. Combined diffusion imaging and MR spectroscopy in the diagnosis of human prion diseases

Author: Jean-Philippe Ranjeva, Jean-Philippe Brandel, Nicholas Ayache, Stéphane Haïk, Didier Dormont, Elsa Kaphan, Jacques Chiras, Patrick J. Cozzone, Marius George Linguraru, Damien Galanaud, Baptiste Faucheux, Centre de résonance magnétique biologique et médicale (CRMBM), Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Analysis and Simulation of Biomedical Images (ASCLEPIOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria), Neurosciences cognitives et imagerie cérébrale (NCIC), Centre National de la Recherche Scientifique (CNRS), Laboratoire d'Imagerie Fonctionnelle (LIF), Université Pierre et Marie Curie - Paris 6 (UPMC)-IFR14-IFR49-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Neuroépidémiologie, Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Marseille (APHM)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Asclepios, Project-Team, Service de Neuroradiologie [CHU Pitié-Salpêtrière], Laboratoire de Neuropathologie Raymond Escourolle, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)
Subjects: In vivo magnetic resonance spectroscopy, Cerebellum/metabolism/pathology, Pathology, Cerebellum, Magnetic Resonance Spectroscopy, [SDV.IB.IMA]Life Sciences [q-bio]/Bioengineering/Imaging, animal diseases, [INFO.INFO-IM] Computer Science [cs]/Medical Imaging, Fluid-attenuated inversion recovery, Pulvinar, Prion Diseases, 030218 nuclear medicine & medical imaging, 0302 clinical medicine, Degenerative disease, [INFO.INFO-TS]Computer Science [cs]/Signal and Image Processing, Cortex (anatomy), Basal ganglia, 80 and over, Corpus Striatum/metabolism/pathology, Prospective Studies, Aged, 80 and over, Brain Diseases, Brain Diseases/metabolism/pathology/physiopathology, Brain, Magnetic Resonance Spectroscopy/*methods, Middle Aged, Frontal Lobe, medicine.anatomical_structure, Adolescent, Adult, Aged, 80 and over, Brain Diseases/metabolism/pathology/physiopathology, Cerebellum/metabolism/pathology, Corpus Striatum/metabolism/pathology, Diffusion Magnetic Resonance Imaging/*methods, Frontal Lobe/metabolism/pathology, Humans, Magnetic Resonance Spectroscopy/*methods, Middle Aged, Prion Diseases/*metabolism/*pathology/physiopathology, Prospective Studies, Pulvinar/metabolism/pathology, Sensitivity and Specificity, [INFO.INFO-MO] Computer Science [cs]/Modeling and Simulation, [SPI.SIGNAL]Engineering Sciences [physics]/Signal and Image processing, Adult, medicine.medical_specialty, Adolescent, [INFO.INFO-TS] Computer Science [cs]/Signal and Image Processing, Prion Diseases/*metabolism/*pathology/physiopathology, Pulvinar/metabolism/pathology, Sensitivity and Specificity, Central nervous system disease, Diffusion Magnetic Resonance Imaging/*methods, 03 medical and health sciences, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Humans, Radiology, Nuclear Medicine and imaging, [SPI.SIGNAL] Engineering Sciences [physics]/Signal and Image processing, Aged, business.industry, Lenticular nucleus, Frontal Lobe/metabolism/pathology, medicine.disease, [INFO.INFO-MO]Computer Science [cs]/Modeling and Simulation, Corpus Striatum, Diffusion Magnetic Resonance Imaging, [SDV.IB.IMA] Life Sciences [q-bio]/Bioengineering/Imaging, Neurology (clinical), business, 030217 neurology & neurosurgery
Abstract: 1936-959X (Electronic) 0195-6108 (Linking) Controlled Clinical Trial Journal Article Research Support, Non-U.S. Gov't; International audience; BACKGROUND AND PURPOSE: The physiopathologic bases underlying the signal intensity changes and reduced diffusibility observed in prion diseases (TSEs) are still poorly understood. We evaluated the interest of MRS combined with DWI both as a diagnostic tool and a way to understand the mechanism underlying signal intensity and ADC changes in this setting. MATERIALS AND METHODS: We designed a prospective study of multimodal MR imaging in patients with suspected TSEs. Forty-five patients with a suspicion of TSE and 11 age-matched healthy volunteers were included. The MR imaging protocol included T1, FLAIR, and DWI sequences. MRS was performed on the cerebellum, pulvinar, right lenticular nucleus, and frontal cortex. MR images were assessed visually, and ADC values were calculated. RESULTS: Among the 45 suspected cases, 31 fulfilled the criteria for probable or definite TSEs (19 sCJDs, 3 iCJDs, 2 vCJDs, and 7 genetic TSEs); and 14 were classified as AltDs. High signals in the cortex and/or basal ganglia were observed in 26/31 patients with TSEs on FLAIR and 29/31 patients on DWI. In the basal ganglia, high DWI signals corresponded to a decreased ADC. Metabolic alterations, increased mIns, and decreased NAA were observed in all patients with TSEs. ADC values and metabolic changes were not correlated; this finding suggests that neuronal stress (vacuolization), neuronal loss, and astrogliosis do not alone explain the decrease of ADC. CONCLUSIONS: MRS combined with other MR imaging is of interest in the diagnosis of TSE and provides useful information for understanding physiopathologic processes underlying prion diseases.
Published: 2010

48. Filamin-A and Myosin VI colocalize with fibrillary Tau protein in Alzheimer's disease and FTDP-17 brains

Author: Annie Laquerrière, Magalie Lecourtois, Sébastien Feuillette, Thierry Frebourg, Charles Duyckaerts, Vincent Deramecourt, Marie-Bernadette Delisle, Luc Buée, Dominique Campion, Claude-Alain Maurage, David Blum, Génétique médicale et fonctionnelle du cancer et des maladies neuropsychiatriques, Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Anatomie et Cytologie Pathologique [CHU Rouen], CHU Rouen, Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU), Laboratoire de Neuropathologie Raymond Escourolle, CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service d'anatomie pathologique et histologie-cytologie [Rangueil], Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-CHU Toulouse [Toulouse]-Hôpital de Rangueil, CHU Toulouse [Toulouse], Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U1172 Inserm - U837 (JPArc), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Lille Nord de France (COMUE)-Université de Lille, Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Centre de Recherche Jean-Pierre AUBERT Neurosciences et Cancer - U837 (JPArc), and Université Lille Nord de France (COMUE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille
Subjects: Male, Filamins, Tau protein, Mice, Transgenic, tau Proteins, macromolecular substances, Filamin, Progressive supranuclear palsy, Mice, 03 medical and health sciences, Contractile Proteins, 0302 clinical medicine, Pick Disease of the Brain, Alzheimer Disease, mental disorders, Myosin, medicine, Animals, Humans, Molecular Biology, ComputingMilieux_MISCELLANEOUS, Aged, 030304 developmental biology, 0303 health sciences, Myosin Heavy Chains, biology, General Neuroscience, Parkinsonism, Microfilament Proteins, Neurodegeneration, Brain, Neurofibrillary Tangles, Middle Aged, medicine.disease, 3. Good health, Cell biology, Tauopathies, Frontotemporal Dementia, biology.protein, Female, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Supranuclear Palsy, Progressive, Neurology (clinical), Tauopathy, Alzheimer's disease, Neuroscience, 030217 neurology & neurosurgery, Chromosomes, Human, Pair 17, Developmental Biology
Abstract: Tauopathies, including Alzheimer's disease (AD), fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP-17), Pick's disease and progressive supranuclear palsy, are neurodegenerative disorders neuropathologically characterized by the presence of intraneuronal fibrillary inclusions composed of abnormally phosphorylated-Tau. Tau protein is a neuronal microtubule-associated protein (MAP) involved in microtubules polymerization and stabilization. So far, the molecular mechanisms underlying Tau-mediated cellular toxicity remain elusive. To address the determinants of Tau neurotoxicity, we previously performed a misexpression screening in a Drosophila tauopathy model to identify genetic modifiers of the human Tau-induced neurodegeneration. We identified several components of the actin network as modifiers of Tau V337M-induced neurodegeneration, i.e. Filamin-A, Myosin VI, Paxillin and Transgelin-3. The aim of this study was to assess whether these genetic interactions were associated with a colocalization of the proteins (i) in the brains of patients with Tau pathologies, and (ii) in the brain of transgenic mice overexpressing human mutant Tau. We found that Filamin-A and Myosin VI indeed colocalize with fibrillary Tau protein in AD and FTDP-17 and in Thy-Tau22 transgenic mice.
Published: 2010

49. COLD PCR HRM: a highly sensitive detection method for IDH1 mutations

Author: Jean-Yves Delattre, Marianne Labussière, Yannick Marie, Blandine Boisselier, Marc Sanson, Virginie Desestret, X Wang, Laurent Capelle, Pietro Ciccarino, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Laboratoire de Neuropathologie Raymond Escourolle, Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Pierre et Marie Curie - Paris 6 (UPMC), Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), UPMC - Département de neurologie 2 - Mazarin, Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Service de Neurologie [CHU Pitié-Salpêtrière], and IFR70-CHU Pitié-Salpêtrière [AP-HP]
Subjects: IDH1, Serial dilution, Biopsy, Mutant, Biology, medicine.disease_cause, Nucleic Acid Denaturation, Polymerase Chain Reaction, High Resolution Melt, 03 medical and health sciences, symbols.namesake, chemistry.chemical_compound, 0302 clinical medicine, Genetics, medicine, Humans, Genetics (clinical), Sanger sequencing, COLD-PCR, Mutation, Life Sciences, Glioma, Molecular biology, Immunohistochemistry, Isocitrate Dehydrogenase, Cold Temperature, chemistry, 030220 oncology & carcinogenesis, symbols, 030217 neurology & neurosurgery, DNA
Abstract: International audience; Isocitrate dehydrogenase 1 R132H (IDH1R132H) mutation is a frequent alteration and a major prognostic marker in gliomas. However, direct sequencing of highly contaminated tumor samples may fail to detect this mutation. Our objective was to evaluated the sensitivity of a newly described amplification method, coamplification at lower temperature-PCR (COLD PCR), combined with high resolution melting (HRM) for the detection of IDH1R132H mutation. To this end, we used serial dilutions of mutant DNA with wild type DNA. PCR-HRM assay detects IDH1R132H mutation at an abundance of 25%, similar to the detection limit of direct Sanger sequencing. Introducing a run of COLD PCR allows the detection of 2% mutant DNA. Using two consecutive runs of COLD PCR, we detected 0.25% mutant DNA in a background of wild type DNA, that mimicks a tumor sample highly contaminated by normal DNA. We then analyzed ten biopsies of tumor edges, considered free of tumor cells by histological analysis, and showed that immunohistochemistry of IDH1R132H was positive in 3 cases (30%), whereas double COLD PCR HRM was positive in the ten cases studied (100%). In summary, COLD PCR HRM analysis is 100-fold more sensitive than Sanger sequencing, rendering this rapid and powerful strategy particularly useful for samples highly contaminated with normal tissue.
Published: 2010

50. Rapid onset frontal leukodystrophy with decreased diffusion coefficient and neuroaxonal spheroids

Author: Françoise Gray, Frédéric Sedel, Olivier Gout, Olivier Lyon-Caen, Jean-Jacques Hauw, Elisabeth Maillart, Marc Polivka, Pierre Labauge, Damien Galanaud, Audrey Rousseau, Service de neuro-pathologie [CHU Pitié-Salpêtrière], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Equipe NEMESIS - Centre de Recherches de l'Institut du Cerveau et de la Moelle épinière (NEMESIS-CRICM), Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de Neuroradiologie [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Unité UMR_S956, Hôpital Lariboisière, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), GHU Garemeau-Nîmes, Laboratoire de Neuropathologie Raymond Escourolle, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC), Expernova, Expernova.com, Pathology Department, VU University Medical Center [Amsterdam], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre], Université Pierre et Marie Curie - Paris 6 (UPMC)-CHU Pitié-Salpêtrière [AP-HP], Université Pierre et Marie Curie - Paris 6 (UPMC)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pierre et Marie Curie - Paris 6 (UPMC), Service de neuro-radiologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Lariboisière-Université Paris Diderot - Paris 7 (UPD7), and CHU Pitié-Salpêtrière [APHP]
Subjects: Adult, medicine.medical_specialty, Pathology, Neurology, Time Factors, Biology, Corpus callosum, Nerve Fibers, Myelinated, Neuroaxonal spheroids, Central nervous system disease, 03 medical and health sciences, 0302 clinical medicine, Degenerative disease, medicine, [INFO.INFO-IM]Computer Science [cs]/Medical Imaging, Effective diffusion coefficient, Humans, 030304 developmental biology, 0303 health sciences, Brain Diseases, integumentary system, Leukodystrophy, medicine.disease, Frontal Lobe, Diffusion Magnetic Resonance Imaging, Rapid onset, Female, Neurology (clinical), 030217 neurology & neurosurgery
Abstract: International audience; Adult leukodystrophies with neuroaxonal spheroids (LNS) constitute a heterogeneous group of genetic diseases. Herein, we report on two unrelated patients with LNS characterized by rapid onset, predominant involvement of the frontal white matter, and areas of decreased apparent diffusion coefficient on diffusion-weighted imaging. We found similar cases in the literature and propose that they represent a distinct entity within the group of LNS. Further studies will be required to identify its molecular basis.
Published: 2009

Catalog

Books, media, physical & digital resources

See catalog results

Searchworks

Select search scope, currently: Articles Catalog books, media & more in Jio Institute collections Articles journal articles & other e-resources

Search

Search Constraints

Refine your results

Search Limiters

Topic

Publication Year Range

Language

Journal

Database

Publisher

69 results on '"Laboratoire de Neuropathologie Raymond Escourolle [CHU Pitié-Salpétriêre]"'

Search Results

Catalog

Select search scope, currently: Articles

Catalog

books, media & more in Jio Institute collections

Articles

journal articles & other e-resources