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12 results on '"MESH: RNA-Binding Protein FUS"'

1. Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

Author

Scekic-Zahirovic, Jelena, Sanjuan-Ruiz, Inmaculada, Kan, Vanessa, Megat, Salim, De Rossi, Pierre, Dieterlé, Stéphane, Cassel, Raphaelle, Jamet, Marguerite, Kessler, Pascal, Wiesner, Diana, Tzeplaeff, Laura, Demais, Valérie, Sahadevan, Sonu, Hembach, Katharina M, Muller, Hans-Peter, Picchiarelli, Gina, Mishra, Nibha, Antonucci, Stefano, Dirrig-Grosch, Sylvie, Kassubek, Jan, Rasche, Volker, Ludolph, Albert, Boutillier, Anne-Laurence, Roselli, Francesco, Polymenidou, Magdalini, Lagier-Tourenne, Clotilde, Liebscher, Sabine, Dupuis, Luc, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Ludwig-Maximilians University [Munich] (LMU), Universität Zürich [Zürich] = University of Zurich (UZH), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), CRBS - Centre de Recherche en Biomédecine de Strasbourg (Inserm UMS38/UNISTRA), University of Ulm (UUlm), Deutsches Zentrum für Neurodegenerative Erkrankungen [Ulm] (DZNE), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), Centre de Neurochimie, Harvard Medical School [Boston] (HMS), Harvard University [Cambridge], Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), Université de Strasbourg Inserm Faculté de médecine, Klinikum der Universitat Munchen, Ludwig-Maximilians-Universität München (LMU), University hospital of Zurich [Zurich], Universität Ulm - Ulm University [Ulm, Allemagne], Massachusetts Institute of Technology (MIT), Ludwig-Maximilians University Hospital (LMU Munich), ANR-16-CE92-0031,EpiFUS,Rôle de FUS dans la régulation des modifications épigénétiques : conséquences pour la sclérose latérale amyotrophique et la démence frontotemporale(2016), ANR-16-CE16-0015,ToFU,Interactions entre TAU, FUS et TDP-43 dans les maladies neurodégénératives(2016), ANR-19-CE17-0016,SPREADALS,Propagation et toxicité des facteurs pathogéniques de la sclérose latérale amyotrophique(2019), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), Anne Laurence, Boutillier, Rôle de FUS dans la régulation des modifications épigénétiques : conséquences pour la sclérose latérale amyotrophique et la démence frontotemporale - - EpiFUS2016 - ANR-16-CE92-0031 - AAPG2016 - VALID, Interactions entre TAU, FUS et TDP-43 dans les maladies neurodégénératives - - ToFU2016 - ANR-16-CE16-0015 - AAPG2016 - VALID, Propagation et toxicité des facteurs pathogéniques de la sclérose latérale amyotrophique - - SPREADALS2019 - ANR-19-CE17-0016 - AAPG2019 - VALID, University of Zurich, Liebscher, Sabine, Dupuis, Luc, Centre de Recherche en Biomédecine de Strasbourg (CRBS), and Dieterle, Stéphane

Subjects
Male, Cytoplasm, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Gene Expression, Synaptic Transmission, MESH: Synapses, Mice, MESH: Animals, Gene Knock-In Techniques, MESH: Amyotrophic Lateral Sclerosis, MESH: Gene Knock-In Techniques, metabolism [RNA-Binding Protein FUS], Motor Neurons, MESH: RNA-Binding Protein FUS, FUS protein, mouse, 3100 General Physics and Astronomy, [SDV] Life Sciences [q-bio], genetics [Amyotrophic Lateral Sclerosis], Phenotype, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, MESH: Motor Neurons, MESH: Mutation, MESH: Gene Expression, Science, 610 Medicine & health, 1600 General Chemistry, Genetics and Molecular Biology, MESH: Phenotype, Article, 1300 General Biochemistry, Genetics and Molecular Biology, MESH: Mice, Inbred C57BL, MESH: Synaptic Transmission, Animals, [SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], MESH: Mice, metabolism [Cytoplasm], metabolism [Amyotrophic Lateral Sclerosis], MESH: Cytoplasm, Amyotrophic Lateral Sclerosis, General Chemistry, metabolism [Motor Neurons], metabolism [Synapses], MESH: Male, Mice, Inbred C57BL, physiology [Synaptic Transmission], General Biochemistry, Mutation, Synapses, RNA-Binding Protein FUS, 11493 Department of Quantitative Biomedicine, genetics [RNA-Binding Protein FUS], MESH: Female
Abstract

Gene mutations causing cytoplasmic mislocalization of the RNA-binding protein FUS lead to severe forms of amyotrophic lateral sclerosis (ALS). Cytoplasmic accumulation of FUS is also observed in other diseases, with unknown consequences. Here, we show that cytoplasmic mislocalization of FUS drives behavioral abnormalities in knock-in mice, including locomotor hyperactivity and alterations in social interactions, in the absence of widespread neuronal loss. Mechanistically, we identified a progressive increase in neuronal activity in the frontal cortex of Fus knock-in mice in vivo, associated with altered synaptic gene expression. Synaptic ultrastructural and morphological defects were more pronounced in inhibitory than excitatory synapses and associated with increased synaptosomal levels of FUS and its RNA targets. Thus, cytoplasmic FUS triggers synaptic deficits, which is leading to increased neuronal activity in frontal cortex and causing related behavioral phenotypes. These results indicate that FUS mislocalization may trigger deleterious phenotypes beyond motor neuron impairment in ALS, likely relevant also for other neurodegenerative diseases characterized by FUS mislocalization., Mutations in the RNA binding protein FUS are associated with ALS. Here the authors show that in FUS knock-in mice there is a progressive increase in neuronal activity in the frontal cortex which is associated with altered synaptic gene expression.

Published
2021

2. Synaptic FUS accumulation triggers early misregulation of synaptic RNAs in a mouse model of ALS

Author

Pierre De Rossi, Marian Hruska-Plochan, Magdalini Polymenidou, Mark D. Robinson, Elena Tantardini, Luc Dupuis, Salim Megat, Julien Weber, Katharina M. Hembach, Petra Schwarz, Sonu Sahadevan, Manuela Pérez-Berlanga, Universität Zürich [Zürich] = University of Zurich (UZH), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University hospital of Zurich [Zurich], Dieterle, Stéphane, University of Zurich, and Polymenidou, Magdalini

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], General Physics and Astronomy, MESH: Synapses, Synapse, Mice, 0302 clinical medicine, MESH: Animals, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, Cerebral Cortex, Multidisciplinary, MESH: RNA-Binding Protein FUS, Neurodegeneration, 10124 Institute of Molecular Life Sciences, 3100 General Physics and Astronomy, Cell biology, [SDV] Life Sciences [q-bio], GABAergic, Microtubule-Associated Proteins, MESH: Cell Nucleus, Science, 1600 General Chemistry, Genetics and Molecular Biology, Biology, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, 1300 General Biochemistry, Genetics and Molecular Biology, MESH: Mice, Inbred C57BL, MESH: RNA, medicine, Animals, RNA, Messenger, Synapse organization, MESH: Mice, MESH: RNA, Messenger, RNA metabolism, Cell Nucleus, Messenger RNA, Amyotrophic Lateral Sclerosis, RNA, General Chemistry, medicine.disease, MESH: Cerebral Cortex, Mice, Inbred C57BL, MESH: Microtubule-Associated Proteins, Disease Models, Animal, 030104 developmental biology, General Biochemistry, Synapses, 570 Life sciences, biology, RNA-Binding Protein FUS, MESH: Disease Models, Animal, 11493 Department of Quantitative Biomedicine, 030217 neurology & neurosurgery, Nuclear localization sequence
Abstract

Mutations disrupting the nuclear localization of the RNA-binding protein FUS characterize a subset of amyotrophic lateral sclerosis patients (ALS-FUS). FUS regulates nuclear RNAs, but its role at the synapse is poorly understood. Using super-resolution imaging we determined that the localization of FUS within synapses occurs predominantly near the vesicle reserve pool of presynaptic sites. Using CLIP-seq on synaptoneurosomes, we identified synaptic FUS RNA targets, encoding proteins associated with synapse organization and plasticity. Significant increase of synaptic FUS during early disease in a mouse model of ALS was accompanied by alterations in density and size of GABAergic synapses. mRNAs abnormally accumulated at the synapses of 6-month-old ALS-FUS mice were enriched for FUS targets and correlated with those depicting increased short-term mRNA stability via binding primarily on multiple exonic sites. Our study indicates that synaptic FUS accumulation in early disease leads to synaptic impairment, potentially representing an initial trigger of neurodegeneration., Mutations in the RNA-binding protein FUS contribute to ALS. Here the authors use CLIP-seq on synaptoneurosomes to identify proteins associated with synapse organization and plasticity that are differentially regulated in a knock-in ALS mouse model.

Published
2021

3. Reversible induction of TDP-43 granules in cortical neurons after traumatic injury

Author

Lilla Tar, Luc Dupuis, Albert C. Ludolph, Akila Chandrasekar, William Tsao, Philip C. Wong, Birgit Linkus, Francesco Roselli, Florian olde Heuvel, Diana Wiesner, University of Ulm (UUlm), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Johns Hopkins University School of Medicine [Baltimore], and Dieterle, Stéphane

Subjects
0301 basic medicine, Pathology, TDP-43, [SDV]Life Sciences [q-bio], Cortical injury, Mice, Superoxide Dismutase-1, 0302 clinical medicine, Brain Injuries, Traumatic, MESH: Behavior, Animal, MESH: Animals, Amyotrophic lateral sclerosis, MESH: Amyotrophic Lateral Sclerosis, MESH: Superoxide Dismutase-1, Motor Neurons, Behavior, Animal, MESH: RNA-Binding Protein FUS, Motor Cortex, Immunohistochemistry, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], Traumatic injury, medicine.anatomical_structure, Neurology, MESH: Motor Neurons, Motor cortex, Genetically modified mouse, medicine.medical_specialty, MESH: Mice, Transgenic, Traumatic brain injury, SOD1, MESH: Brain Injuries, Traumatic, Mice, Transgenic, MESH: Cytoplasmic Granules, Biology, Cytoplasmic Granules, MESH: Motor Cortex, 03 medical and health sciences, Developmental Neuroscience, Autophagy, medicine, Animals, MESH: Autophagy, MESH: Mice, Amyotrophic Lateral Sclerosis, Colocalization, MESH: Immunohistochemistry, medicine.disease, nervous system diseases, Disease Models, Animal, 030104 developmental biology, RNA-Binding Protein FUS, ALS, MESH: Disease Models, Animal, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery
Abstract

International audience; Traumatic brain injury (TBI) has been proposed as a risk factor for neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To determine whether TBI might trigger or exacerbate ALS-relevant pathology, we delivered a mild stab-wound injury to the motor cortex of three different ALS mouse models expressing mutations in SOD1, TDP-43 or FUS and scrutinized the effects on the formation of phospho-TDP-43 (pTDP-43) cytoplasmic granules. Stab-injury induced the formation of cytoplasmic TDP-43 granules in wt animals, peaking at 3dpi; a much larger response was seen in mutant TDP-43 mice, whose response peaked at 7dpi. The pTDP-43 granules did not colocalize with the stress markers TIAR-1 and FUS but colocalized with FMRP (35%) and with p62 (65%), suggesting their involvement in transport granules and their clearance by autophagy. A similar, albeit smaller effect, was seen in mutant FUS mice. In the SOD1G93A mouse model, neither increase in pTDP-43 granules nor in SOD1 aggregates were detected. In all cases, pTDP-43 granules were cleared and the number of pTDP-43-positive neurons returned to baseline by 40dpi. Neither injury-related neuronal loss nor motor performance or survival was significantly different in transgenic mice receiving injury vs sham mice. Thus, trauma can trigger ALS-related TDP-43 pathology, the extent of which is modulated by ALS-related mutations. However, the pathological findings prove reversible and do not affect disease progression and neuronal vulnerability.

Published
2018

4. Hypertonic Stress Causes Cytoplasmic Translocation of Neuronal, but Not Astrocytic, FUS due to Impaired Transportin Function

Author

Dorothee Dormann, Stefan Reber, Luc Dupuis, Helena Ederle, Marian Hruska-Plochan, Eva-Maria Hock, Marc-David Ruepp, Florent Laferrière, Zuzanna Maniecka, Lucas Pelkmans, M K Sonu Sahadevan, Tammaryn Lashley, Lauren M. Gittings, Magdalini Polymenidou, Dieterle, Stéphane, Universität Zürich [Zürich] = University of Zurich (UZH), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), University of Bern, Ludwig Maximilian University [Munich] (LMU), UCL, Institute of Neurology [London], Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), UK Dementia Research Institute (UK DRI), University College of London [London] (UCL), Universität Bern [Bern], Ludwig-Maximilians-Universität München (LMU), Institute of Neurology [London], King‘s College London, Universität Bern [Bern] (UNIBE), Laferriere, Florent, University of Zurich, and Polymenidou, Magdalini

Subjects
0301 basic medicine, Cytoplasm, MESH: Hippocampus, Cytoplasmic inclusion, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, [SDV]Life Sciences [q-bio], MESH: Neurons, Chromosomal translocation, RNA-binding protein, RNA-binding proteins, Hippocampus, Mice, ALS, FTD, FUS, stress granules, nucleocytoplasmic shuttling, Transportin, protein aggregation, MESH: Animals, Amyotrophic lateral sclerosis, Cerebral Cortex, Neurons, Chemistry, MESH: RNA-Binding Protein FUS, Cell biology, [SDV] Life Sciences [q-bio], MESH: HEK293 Cells, Transportin 1, MESH: Cell Nucleus, 610 Medicine & health, Genetics and Molecular Biology, Karyopherins, Transfection, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Stress granule, 1300 General Biochemistry, Genetics and Molecular Biology, MESH: Mice, Inbred C57BL, medicine, Animals, Humans, MESH: Mice, Cell Nucleus, MESH: Humans, MESH: Cytoplasm, MESH: Transfection, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, medicine.disease, MESH: Karyopherins, MESH: Cerebral Cortex, Mice, Inbred C57BL, MESH: Astrocytes, HEK293 Cells, 030104 developmental biology, Hypertonic Stress, Astrocytes, General Biochemistry, RNA-Binding Protein FUS, 11493 Department of Quantitative Biomedicine
Abstract

The primarily nuclear RNA-binding protein FUS (fused in sarcoma) forms pathological cytoplasmic inclusions in a subset of early-onset amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) patients. In response to cellular stress, FUS is recruited to cytoplasmic stress granules, which are hypothesized to act as precursors of pathological inclusions. We monitored the stress-induced nucleocytoplasmic shuttling of endogenous FUS in an ex vivo mouse CNS model and human neural networks. We found that hyperosmolar, but not oxidative, stress induced robust cytoplasmic translocation of neuronal FUS, with transient nuclear clearance and loss of function. Surprisingly, this reaction is independent of stress granule formation and the molecular pathways activated by hyperosmolarity. Instead, it represents a mechanism mediated by cytoplasmic redistribution of Transportin 1/2 and is potentiated by transcriptional inhibition. Importantly, astrocytes, which remain unaffected in ALS/FTD-FUS, are spared from this stress reaction that may signify the initial event in the development of FUS pathology., Cell Reports, 24 (4), ISSN:2666-3864, ISSN:2211-1247

Published
2018

5. Dysregulation of chromatin remodelling complexes in amyotrophic lateral sclerosis

Author

Ekaterina Rogaeva, Julia Keith, Janice Robertson, Heather D. Durham, Benoit J. Gentil, Christine Marques, Beibei Zhao, Caroline Rouaux, Lorne Zinman, Sandra Minotti, Michael Tibshirani, McGill University = Université McGill [Montréal, Canada], University of Toronto, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), and Dieterle, Stéphane

Subjects
0301 basic medicine, Cytoplasm, [SDV]Life Sciences [q-bio], Mutant, MESH: Neurons, MESH: DNA Helicases, medicine.disease_cause, MESH: Spinal Cord, Mice, 0302 clinical medicine, MESH: Animals, Amyotrophic lateral sclerosis, Genetics (clinical), MESH: Amyotrophic Lateral Sclerosis, Motor Neurons, Neurons, Mutation, MESH: RNA-Binding Protein FUS, Nuclear Proteins, Cell Differentiation, General Medicine, MESH: Transcription Factors, MESH: Protein Subunits, Cell biology, DNA-Binding Proteins, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Spinal Cord, MESH: Motor Neurons, MESH: Cell Differentiation, MESH: Mutation, Protein subunit, Biology, 03 medical and health sciences, Genetics, medicine, Animals, Humans, Molecular Biology, MESH: Mice, Messenger RNA, MESH: Humans, MESH: Cytoplasm, Amyotrophic Lateral Sclerosis, DNA Helicases, MESH: Chromatin Assembly and Disassembly, Motor neuron, Chromatin Assembly and Disassembly, Spinal cord, medicine.disease, Protein Subunits, 030104 developmental biology, RNA-Binding Protein FUS, MESH: Nuclear Proteins, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins, Transcription Factors
Abstract

International audience; Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with paralysis resulting from dysfunction and loss of motor neurons. A common neuropathological finding is attrition of motor neuron dendrites, which make central connections vital to motor control. The chromatin remodelling complex, neuronal Brahma-related gene 1 (Brg1)-associated factor complex (nBAF), is critical for neuronal differentiation, dendritic extension and synaptic function. We have identified loss of the crucial nBAF subunits Brg1, Brg1-associated factor 53b and calcium responsive transactivator in cultured motor neurons expressing FUS or TAR-DNA Binding Protein 43 (TDP-43) mutants linked to familial ALS. When plasmids encoding wild-type or mutant human FUS or TDP-43 were expressed in motor neurons of dissociated spinal cord cultures prepared from E13 mice, mutant proteins in particular accumulated in the cytoplasm. Immunolabelling of nBAF subunits was reduced in proportion to loss of nuclear FUS or TDP-43 and depletion of Brg1 was associated with nuclear retention of Brg1 mRNA. Dendritic attrition (loss of intermediate and terminal dendritic branches) occurred in motor neurons expressing mutant, but not wild-type, FUS or TDP-43. This attrition was delayed by ectopic over-expression of Brg1 and was reproduced by inhibiting Brg1 activity either through genetic manipulation or treatment with the chemical inhibitor, (E)-1-(2-Hydroxyphenyl)-3-((1R, 4R)-5-(pyridin-2-yl)-2, 5-diazabicyclo[2.2.1]heptan-2-yl)prop-2-en-1-one, demonstrating the importance of Brg1 to maintenance of dendritic architecture. Loss of nBAF subunits was also documented in spinal motor neurons in autopsy tissue from familial amyotrophic sclerosis (chromosome 9 open reading frame 72 with G4C2 nucleotide expansion) and from sporadic cases with no identified mutation, pointing to dysfunction of nBAF chromatin remodelling in multiple forms of ALS.

Published
2017

6. ALS-causing mutations differentially affect PGC-1α expression and function in the brain vs. peripheral tissues

Author

Anke Witting, Eva Buck, Tanja Lucas, Jasmin Sprissler, Karin M Danzer, Karlheinz Holzmann, Kerstin Lang, Lara Barteczko, Tobias M. Boeckers, Patrick Weydt, Maria Demestre, Luc Dupuis, Hanna Bayer, Katrin S. Lindenberg, Noemi Pasquarelli, Julia Higelin, Albert C. Ludolph, University of Ulm (UUlm), Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Bonn, and Dieterle, Stéphane

Subjects
0301 basic medicine, [SDV]Life Sciences [q-bio], MESH: Neurons, PGC-1α, MESH: Protein Isoforms, [SCCO]Cognitive science, Superoxide Dismutase-1, 0302 clinical medicine, Adipose Tissue, Brown, Neurotrophic factors, Protein Isoforms, MESH: Animals, Amyotrophic lateral sclerosis, Induced pluripotent stem cell, MESH: Amyotrophic Lateral Sclerosis, MESH: Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, MESH: Superoxide Dismutase-1, Neurons, MESH: Muscle, Skeletal, MESH: RNA-Binding Protein FUS, Neurodegeneration, Brain, SOD1, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha, [SDV] Life Sciences [q-bio], Neurology, PPARGC1A, MESH: Mutation, MESH: Rats, MESH: Mice, Transgenic, Induced Pluripotent Stem Cells, Mice, Transgenic, MESH: Zebrafish Proteins, Biology, MESH: Induced Pluripotent Stem Cells, Neuroprotection, MESH: Adipose Tissue, Brown, Cell Line, lcsh:RC321-571, 03 medical and health sciences, MESH: Brain, Lou Gehrig disease, MESH: Mice, Inbred C57BL, Coactivator, medicine, Animals, Humans, RNA, Messenger, Muscle, Skeletal, MESH: Zebrafish, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, FUS, MESH: RNA, Messenger, MESH: Humans, [SCCO] Cognitive science, medicine.disease, Rats, MESH: Cell Line, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, Mutation, Cancer research, RNA-Binding Protein FUS, Lactate, MESH: Disease Models, Animal, 030217 neurology & neurosurgery
Abstract

International audience; Background: Monogenetic forms of amyotrophic lateral sclerosis (ALS) offer an opportunity for unraveling the molecular mechanisms underlying this devastating neurodegenerative disorder. In order to identify a link between ALS-related metabolic changes and neurodegeneration, we investigated whether ALS-causing mutations interfere with the peripheral and brain-specific expression and signaling of the metabolic master regulator PGC (PPAR gamma coactivator)-1α (PGC-1α).Methods: We analyzed the expression of PGC-1α isoforms and target genes in two mouse models of familial ALS and validated the stimulated PGC-1α signaling in primary adipocytes and neurons of these animal models and in iPS derived motoneurons of two ALS patients harboring two different frame-shift FUS/TLS mutations.Results: Mutations in SOD1 and FUS/TLS decrease Ppargc1a levels in the CNS whereas in muscle and brown adipose tissue Ppargc1a mRNA levels were increased. Probing the underlying mechanism in neurons, we identified the monocarboxylate lactate as a previously unrecognized potent and selective inducer of the CNS-specific PGC-1α isoforms. Lactate also induced genes like brain-derived neurotrophic factor, transcription factor EB and superoxide dismutase 3 that are down-regulated in PGC-1α deficient neurons. The lactate-induced CNS-specific PGC-1α signaling system is completely silenced in motoneurons derived from induced pluripotent stem cells obtained from two ALS patients harboring two different frame-shift FUS/TLS mutations.Conclusion: ALS mutations increase the canonical PGC-1α system in the periphery while inhibiting the CNS-specific isoforms. We identify lactate as an inducer of the neuronal PGC-1α system directly linking brain metabolism and neuroprotection. Changes in the PGC-1α system might be involved in the ALS accompanied metabolic changes and in neurodegeneration.

Published
2017

7. Toxic gain of function from mutant FUS protein is crucial to trigger cell autonomous motor neuron loss

Author

Kevin Drenner, Jérôme Sinniger, Mélanie Jambeau, Oliver Sendscheid, Anke Witting, Jelena Scekic-Zahirovic, Tatyana A. Shelkovnikova, Marie-Christine Birling, Albert C. Ludolph, Erik Storkebaum, Sina Mersmann, Caroline Rouaux, Clotilde Lagier-Tourenne, Marina Wagner, Stéphane Dieterlé, Luc Dupuis, Xiang-Dong Fu, Hajer El Oussini, Ying Sun, Hairi Li, Friedemann Kiefer, Yu Zhou, Jinsong Qiu, Sylvie Dirrig-Grosch, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft, University of California [San Diego] (UC San Diego), University of California, Institut Clinique de la Souris (ICS), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), School of Psychology [Cardiff University], Cardiff University, University of Ulm (UUlm), Ludwig Institute for Cancer Research, Dieterle, Stéphane, and University of California (UC)

Subjects
0301 basic medicine, Cytoplasm, amyotrophic lateral sclerosis, PY‐NLS, motor neuron degeneration, [SDV]Life Sciences [q-bio], Mutant, Inbred C57BL, frontotemporal dementia, Medical and Health Sciences, Transgenic, MESH: Spinal Cord, MESH: Heart Conduction System, [SCCO]Cognitive science, Mice, 0302 clinical medicine, Gene expression, News & Views, MESH: Animals, MESH: Xenopus, Amyotrophic lateral sclerosis, Genetics, Motor Neurons, MESH: Middle Aged, MESH: RNA-Binding Protein FUS, General Neuroscience, Neurodegeneration, Brain, Biological Sciences, Cell biology, [SDV] Life Sciences [q-bio], medicine.anatomical_structure, Spinal Cord, MESH: HEK293 Cells, Knockout mouse, MESH: Nucleotide Motifs, MESH: Motor Neurons, MESH: Mutation, MESH: Myotonic Dystrophy, MESH: Mice, Transgenic, Mice, Transgenic, Biology, PY-NLS, General Biochemistry, Genetics and Molecular Biology, MESH: Sodium Channels, 03 medical and health sciences, MESH: Brain, MESH: Mice, Inbred C57BL, Information and Computing Sciences, medicine, Animals, Molecular Biology, Loss function, FUS, MESH: Humans, MESH: Molecular Sequence Data, General Immunology and Microbiology, MESH: Cytoplasm, MESH: NAV1.5 Voltage-Gated Sodium Channel, [SCCO] Cognitive science, Motor neuron, medicine.disease, MESH: Male, Mice, Inbred C57BL, 030104 developmental biology, MESH: RNA-Binding Proteins, Mutation, RC0321, RNA-Binding Protein FUS, MESH: Exons, MESH: Female, 030217 neurology & neurosurgery, Developmental Biology
Abstract

International audience; FUS is an RNA-binding protein involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Cytoplasmic FUS-containing aggregates are often associated with concomitant loss of nuclear FUS Whether loss of nuclear FUS function, gain of a cytoplasmic function, or a combination of both lead to neurodegeneration remains elusive. To address this question, we generated knockin mice expressing mislocalized cytoplasmic FUS and complete FUS knockout mice. Both mouse models display similar perinatal lethality with respiratory insufficiency, reduced body weight and length, and largely similar alterations in gene expression and mRNA splicing patterns, indicating that mislocalized FUS results in loss of its normal function. However, FUS knockin mice, but not FUS knockout mice, display reduced motor neuron numbers at birth, associated with enhanced motor neuron apoptosis, which can be rescued by cell-specific CRE-mediated expression of wild-type FUS within motor neurons. Together, our findings indicate that cytoplasmic FUS mislocalization not only leads to nuclear loss of function, but also triggers motor neuron death through a toxic gain of function within motor neurons.

Published
2016

8. Delocalization of the multifunctional RNA splicing factor TLS/FUS in hippocampal neurones: exclusion from the nucleus and accumulation in dendritic granules and spine heads

Author

Yves Goldberg, Agnès Belly, Rémy Sadoul, Françoise Moreau-Gachelin, Neurodegenerescence et Plasticite, Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), Transduction du signal et oncogénèse, Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Curie, Département réponse et dynamique cellulaire (DRDC), Institut National de la Recherche Agronomique (INRA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Work funded by the INSERM and by ACI Télémédecine (image analysis)., Fraboulet, Sandrine, and Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
MESH: Hippocampus, Dendritic spine, RNA-binding protein, MESH: Neurons, Fluorescent Antibody Technique, neuronal mRNA traffic, Hippocampal formation, Hippocampus, 0302 clinical medicine, MESH: Animals, Nuclear protein, MESH: Fluorescent Antibody Technique, Cells, Cultured, Neurons, 0303 health sciences, MESH: RNA-Binding Protein FUS, General Neuroscience, RNA-Binding Proteins, Cell biology, DNA-Binding Proteins, medicine.anatomical_structure, RNA splicing, MESH: Cell Fractionation, Microtubule-Associated Proteins, MESH: Cells, Cultured, MESH: Cell Nucleus, MESH: Rats, Dendritic Spines, Blotting, Western, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, Biology, Cell Fractionation, MESH: Actins, Receptors, N-Methyl-D-Aspartate, MESH: Dendritic Spines, 03 medical and health sciences, neuronespecific splicing, medicine, Animals, Humans, MESH: Blotting, Western, [SDV.BC] Life Sciences [q-bio]/Cellular Biology, Adaptor Proteins, Signal Transducing, MESH: Adaptor Proteins, Signal Transducing, 030304 developmental biology, Cell Nucleus, MESH: Receptors, N-Methyl-D-Aspartate, Messenger RNA, MESH: Humans, dendritic mRNAs, MESH: Embryo, Mammalian, RNA, Embryo, Mammalian, Actins, Rats, MESH: Microtubule-Associated Proteins, MESH: RNA-Binding Proteins, RNA-Binding Protein FUS, Nucleus, Neuroscience, MESH: DNA-Binding Proteins, 030217 neurology & neurosurgery
Abstract

International audience; Long-term synaptic change in the cortex and the hippocampus is believed to require the highly localized delivery and translation of mRNAs in the dendritic shafts and spines. The molecular interactions that underlie local signalling between synapses and mRNAs are still largely undefined. After purification from total brain extracts, the NMDA receptor is known to be associated with numerous proteins, including the multifunctional RNA-binding factor TLS (also called FUS). In non-neural tissue, TLS is a vital nuclear protein with roles in DNA repair, homologous recombination, transcriptional regulation and pre-mRNA processing. We have examined the distribution of TLS in hippocampal neurones, both in the adult brain and in mature primary cultures, using subcellular fractionation and immunofluorescence techniques. TLS immunoreactivity is largely excluded from the neuronal nucleus and is found in the cytosol and in somatodendritic particles. In some of these particles, TLS colocalizes with Sam68, a nuclear RNA-binding protein that we previously showed is incorporated into dendritic RNA granules. Some of the TLS clusters also colocalize with NMDA receptor clusters. Finally, TLS clusters are occasionally seen within spine heads. The apparent removal of TLS from the nucleus might result in specific patterns of mRNA transcription or splicing in hippocampal neurones. TLS may also contribute to steering, anchoring or regulating mRNAs at synaptic sites.

Published
2005

9. FUS stimulates microRNA biogenesis by facilitating co-transcriptional Drosha recruitment

Author

Morlando, Mariangela, Dini Modigliani, Stefano, Torrelli, Giulia, Rosa, Alessandro, Di Carlo, Valerio, Caffarelli, Elisa, Bozzoni, Irene, Department of Biology and Biotechnology 'Charles Darwin', Institut Pasteur, Fondation Cenci Bolognetti - Istituto Pasteur Italia, Fondazione Cenci Bolognetti, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Institute of Molecular Biology and Pathology, CNR, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Center for Life Nano Science at Sapienza, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome]-Istituto Italiano di Tecnologia (IIT), Réseau International des Instituts Pasteur (RIIP), and This work was partially supported by grants from: Telethon (GGP07049), Parent Project Italia, AIRC, IIT 'SEED', FIRB, PRIN and BEMM.

Subjects
Ribonuclease III, Chromatin Immunoprecipitation, MESH: Cell Line, Tumor, Blotting, Western, MESH: Neurons, Oligonucleotides, Electrophoretic Mobility Shift Assay, microRNA biogenesis, Real-Time Polymerase Chain Reaction, Article, MESH: Synapses, MESH: Chromatin, Drosha, Cell Line, MESH: Ribonuclease III, MESH: Plasmids, MESH: Oligonucleotides, Cell Line, Tumor, MESH: Blotting, Western, Humans, Immunoprecipitation, FUS, ALS, chromatin immunoprecipitation, FUS/TLS, microRNA, Chromatin, MicroRNAs, Neurons, Plasmids, RNA-Binding Protein FUS, Synapses, MESH: Chromatin Immunoprecipitation, MESH: Humans, Tumor, MESH: RNA-Binding Protein FUS, MESH: Real-Time Polymerase Chain Reaction, MESH: Immunoprecipitation, Blotting, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, als, drosha, fus/tls, microrna, MESH: Electrophoretic Mobility Shift Assay, MESH: MicroRNAs, Western
Abstract

International audience; microRNA abundance has been shown to depend on the amount of the microprocessor components or, in some cases, on specific auxiliary co-factors. In this paper, we show that the FUS/TLS (fused in sarcoma/translocated in liposarcoma) protein, associated with familial forms of Amyotrophic Lateral Sclerosis (ALS), contributes to the biogenesis of a specific subset of microRNAs. Among them, species with roles in neuronal function, differentiation and synaptogenesis were identified. We also show that FUS/TLS is recruited to chromatin at sites of their transcription and binds the corresponding pri-microRNAs. Moreover, FUS/TLS depletion leads to decreased Drosha level at the same chromatin loci. Limited FUS/TLS depletion leads to a reduced microRNA biogenesis and we suggest a possible link between FUS mutations affecting nuclear/cytoplasmic partitioning of the protein and altered neuronal microRNA biogenesis in ALS pathogenesis.

Published
2012

10. 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

11. FUS mutations in frontotemporal lobar degeneration with amyotrophic lateral sclerosis

Author

Broustal, Oriane, Camuzat, Agnès, Guillot-Noël, Lena, Guy, Nathalie, Millecamps, Stéphanie, Deffond, Didier, Lacomblez, Lucette, Golfier, Véronique, Hannequin, Didier, Salachas, François, Camu, William, Didic, Mira, Dubois, Bruno, Meininger, Vincent, Le Ber, Isabelle, Brice, Alexis, Clinical And Genetic Research Network On Ftd/ftd-Mnd, French, 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), 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), Génétique du cancer et des maladies neuropsychiatriques (GMFC), Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Normandie Université (NU)-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), Centre référent Sclérose Latérale Amyotrophique [CHRU Montpellier] (SLA CHRU Montpellier), Université Montpellier 1 (UM1)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Service de neurologie et de neuropsychologie, Université de la Méditerranée - Aix-Marseille 2-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), Neuroépidémiologie Tropicale et Comparée (NETEC), Université de Limoges (UNILIM)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503), 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), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Université Montpellier 1 (UM1), Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génomique, Environnement, Immunité, Santé, Thérapeutique (GEIST FR CNRS 3503)-Institut d'Epidémiologie Neurologique et de Neurologie Tropicale-Université de Limoges (UNILIM), 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 Grelier, Elisabeth

Subjects
Male, MESH: Pedigree, Mutation, Missense, MESH: Phenotype, mental disorders, Humans, MESH: Amyotrophic Lateral Sclerosis, Aged, MESH: Aged, MESH: Mutation, Missense, MESH: Humans, MESH: Middle Aged, MESH: RNA-Binding Protein FUS, Amyotrophic Lateral Sclerosis, nutritional and metabolic diseases, Middle Aged, MESH: Male, Pedigree, nervous system diseases, Phenotype, [SDV.SPEE] Life Sciences [q-bio]/Santé publique et épidémiologie, RNA-Binding Protein FUS, Female, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, MESH: Frontotemporal Lobar Degeneration, Frontotemporal Lobar Degeneration, MESH: Female
Abstract

International audience; Rapid advances were made in the knowledge of amyotrophic lateral sclerosis (ALS) with the recent identification of TARDBP and FUS mutations in familial ALS. More recently, FUS-positive inclusions were found in a subset of TDP-43-negative frontotemporal lobar degeneration (FTLD) prompting us to analyze FUS in FTLD and FTLD-ALS patients. The p.Arg521His mutation was identified in a patient who initially had behavioral disorders and rapidly developed ALS. Although the frequency of mutations is low, our study enlarges the phenotypes associated with FUS mutations and shows that FUS could also play a direct pathogenic role in FTLD spectrum of diseases.

Published
2010

12. Motor neuron intrinsic and extrinsic mechanisms contribute to the pathogenesis of FUS-associated amyotrophic lateral sclerosis

Author

Frédérique René, K. Allmeroth, Albert C. Ludolph, Marina Wagner, Christian Haass, Erik Storkebaum, Luc Dupuis, Ying Sun, Sylvie Dirrig-Grosch, Sina Mersmann, Dorothee Dormann, Stéphane Dieterlé, Jelena Scekic-Zahirovic, Kevin Drenner, Jérôme Sinniger, Clotilde Lagier-Tourenne, Hajer El Oussini, Mécanismes Centraux et Périphériques de la Neurodégénérescence, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Max Planck Institute for Molecular Biomedicine, Max-Planck-Gesellschaft, University of Münster, Ludwig Institute for Cancer Research, Ludwig-Maximilians-Universität München (LMU), Munich Cluster for systems neurology [Munich] (SyNergy), Technische Universität München [München] (TUM)-Ludwig-Maximilians-Universität München (LMU), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Ulm (UUlm), Massachusetts General Hospital [Boston], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU), and Dieterle, Stéphane

Subjects
Male, 0301 basic medicine, Cytoplasm, Pathology, metabolism [Muscle, Skeletal], pathology [Cytoplasm], [SDV]Life Sciences [q-bio], RNA-binding proteins, metabolism [Axons], Fronto-temporal dementia, Mouse models, medicine.disease_cause, MESH: Nerve Degeneration, pathology [Muscle, Skeletal], MESH: Spinal Cord, Pathogenesis, [SCCO]Cognitive science, 0302 clinical medicine, MESH: Animals, Amyotrophic lateral sclerosis, metabolism [Nerve Degeneration], MESH: Amyotrophic Lateral Sclerosis, Motor Neurons, metabolism [RNA-Binding Protein FUS], MESH: Muscle, Skeletal, Mutation, pathology [Axons], MESH: RNA-Binding Protein FUS, FUS protein, mouse, pathology [Nerve Degeneration], MESH: Oligodendroglia, Phenotype, Null allele, MESH: Motor Activity, 3. Good health, [SDV] Life Sciences [q-bio], Oligodendroglia, physiology [Motor Activity], medicine.anatomical_structure, Spinal Cord, MESH: Motor Neurons, metabolism [Spinal Cord], MESH: Axons, medicine.medical_specialty, MESH: Mutation, pathology [Motor Neurons], MESH: Mice, Transgenic, Clinical Neurology, Mice, Transgenic, pathology [Spinal Cord], Motor Activity, Biology, metabolism [RNA, Messenger], Pathology and Forensic Medicine, metabolism [Oligodendroglia], 03 medical and health sciences, Cellular and Molecular Neuroscience, Downregulation and upregulation, MESH: Mice, Inbred C57BL, medicine, Animals, ddc:610, RNA, Messenger, Muscle, Skeletal, pathology [Amyotrophic Lateral Sclerosis], metabolism [Cytoplasm], MESH: RNA, Messenger, Original Paper, metabolism [Amyotrophic Lateral Sclerosis], MESH: Cytoplasm, [SCCO] Cognitive science, metabolism [Motor Neurons], Motor neuron, innervation [Muscle, Skeletal], Spinal cord, medicine.disease, Axons, Non-cell autonomous mechanisms, MESH: Male, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, pathology [Oligodendroglia], Nerve Degeneration, RNA-Binding Protein FUS, Neurology (clinical), MESH: Disease Models, Animal, genetics [RNA-Binding Protein FUS], Neuroscience, 030217 neurology & neurosurgery
Abstract

Motor neuron-extrinsic mechanisms have been shown to participate in the pathogenesis of ALS-SOD1, one familial form of amyotrophic lateral sclerosis (ALS). It remains unclear whether such mechanisms contribute to other familial forms, such as TDP-43 and FUS-associated ALS. Here, we characterize a single-copy mouse model of ALS-FUS that conditionally expresses a disease-relevant truncating FUS mutant from the endogenous murine Fus gene. We show that these mice, but not mice heterozygous for a Fus null allele, develop similar pathology as ALS-FUS patients and a mild motor neuron phenotype. Most importantly, CRE-mediated rescue of the Fus mutation within motor neurons prevented degeneration of motor neuron cell bodies, but only delayed appearance of motor symptoms. Indeed, we observed downregulation of multiple myelin-related genes, and increased numbers of oligodendrocytes in the spinal cord supporting their contribution to behavioral deficits. In all, we show that mutant FUS triggers toxic events in both motor neurons and neighboring cells to elicit motor neuron disease. Electronic supplementary material The online version of this article (doi:10.1007/s00401-017-1687-9) contains supplementary material, which is available to authorized users.

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