85 results on '"Dufour, Noëlle"'
Search Results
2. Mono- and Biallelic Inactivation of Huntingtin Gene in Patient-Specific Induced Pluripotent Stem Cells Reveal HTT Roles in Striatal Development and Neuronal Functions.
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Louessard, Morgane, Cailleret, Michel, Jarrige, Margot, Bigarreau, Julie, Lenoir, Sophie, Dufour, Noëlle, Rey, Maria, Saudou, Frédéric, Deglon, Nicole, and Perrier, Anselme L.
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PLURIPOTENT stem cells ,GENE silencing ,HUNTINGTON disease ,CELL physiology ,INDUCED pluripotent stem cells - Abstract
Background: Mutations in the Huntingtin (HTT) gene cause Huntington's disease (HD), a neurodegenerative disorder. As a scaffold protein, HTT is involved in numerous cellular functions, but its normal and pathogenic functions during human forebrain development are poorly understood. Objective: To investigate the developmental component of HD, with a specific emphasis on understanding the functions of wild-type and mutant HTT alleles during forebrain neuron development in individuals carrying HD mutations. Methods: We used CRISPR/Cas9 gene-editing technology to disrupt the ATG region of the HTT gene via non-homologous end joining to produce mono- or biallelic HTT knock-out human induced pluripotent stem cell (iPSC) clones. Results: We showed that the loss of wild-type, mutant, or both HTT isoforms does not affect the pluripotency of iPSCs or their transition into neural cells. However, we observed that HTT loss causes division impairments in forebrain neuro-epithelial cells and alters maturation of striatal projection neurons (SPNs) particularly in the acquisition of DARPP32 expression, a key functional marker of SPNs. Finally, young post-mitotic neurons derived from HTT-/- human iPSCs display cellular dysfunctions observed in adult HD neurons. Conclusions: We described a novel collection of isogenic clones with mono- and biallelic HTT inactivation that complement existing HD-hiPSC isogenic series to explore HTT functions and test therapeutic strategies in particular HTT-lowering drugs. Characterizing neural and neuronal derivatives from human iPSCs of this collection, we show evidence that HTT loss or mutation has impacts on neuro-epithelial and striatal neurons maturation, and on basal DNA damage and BDNF axonal transport in post-mitotic neurons. [ABSTRACT FROM AUTHOR]
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- 2024
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3. Reactive astrocytes promote proteostasis in Huntington's disease through the JAK2-STAT3 pathway.
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Abjean, Laurene, Haim, Lucile Ben, Riquelme-Perez, Miriam, Gipchtein, Pauline, Derbois, Céline, Palomares, Marie-Ange, Petit, Fanny, Hérard, Anne-Sophie, Gaillard, Marie-Claude, Guillermier, Martine, Gaudin-Guérif, Mylène, Aurégan, Gwennaëlle, Sagar, Nisrine, Héry, Cameron, Dufour, Noëlle, Robil, Noémie, Kabani, Mehdi, Melki, Ronald, Grange, Pierre De la, and Bemelmans, Alexis P
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HUNTINGTON disease ,ASTROCYTES ,STILL'S disease ,MAGNETIC resonance imaging ,VIRAL genes - Abstract
Huntington's disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington's disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington's disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington's disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington's disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington's disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes. [ABSTRACT FROM AUTHOR]
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- 2023
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4. Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntingtonʼs disease
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Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Jan, Caroline, Dufour, Noëlle, Hantraye, Philippe, Elalouf, Jean-Marc, De Chaldée, Michel, Déglon, Nicole, and Brouillet, Emmanuel
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- 2015
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5. The striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo
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Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Petit, Fanny, Bernay, Benoît, Guillermier, Martine, Bonvento, Gilles, Dufour, Noëlle, Elalouf, Jean-Marc, Hantraye, Philippe, Déglon, Nicole, de Chaldée, Michel, and Brouillet, Emmanuel
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- 2015
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6. Overexpression of the autophagic beclin-1 protein clears mutant ataxin-3 and alleviates Machado–Joseph disease
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Nascimento-Ferreira, Isabel, Santos-Ferreira, Tiago, Sousa-Ferreira, Lígia, Auregan, Gwennaëlle, Onofre, Isabel, Alves, Sandro, Dufour, Noëlle, Colomer Gould, Veronica F., Koeppen, Arnulf, Déglon, Nicole, and Pereira de Almeida, Luís
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- 2011
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7. Silencing ataxin-3 mitigates degeneration in a rat model of Machado–Joseph disease: no role for wild-type ataxin-3?
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Alves, Sandro, Nascimento-Ferreira, Isabel, Dufour, Noëlle, Hassig, Raymonde, Auregan, Gwennaëlle, Nóbrega, Clévio, Brouillet, Emmanuel, Hantraye, Philippe, Pedroso de Lima, Maria C., Déglon, Nicole, and de Almeida, Luís Pereira
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- 2010
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8. Capucin does not modify the toxicity of a mutant Huntingtin fragment in vivo
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Galvan, Laurie, Lepejová, Nad'a, Gaillard, Marie-Claude, Malgorn, Carole, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Dufour, Noëlle, Héry, Patrick, Gérard, Matthieu, Elalouf, Jean-Marc, Déglon, Nicole, Brouillet, Emmanuel, and de Chaldée, Michel
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- 2012
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9. The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin
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Galvan, Laurie, Francelle, Laetitia, Gaillard, Marie-Claude, De Longprez, Lucie, Carrillo-de Sauvage, Maria-Angeles, Liot, Géraldine, Cambon, Karine, Stimmer, Lev, Luccantoni, Sophie, Flament, Julien, Valette, Julien, De Chaldée, Michel, Auregan, Gwenaëlle, Guillermier, Martine, Joséphine, Charlène, Petit, Fanny, Jan, Caroline, Jarrige, Margot, Dufour, Noëlle, Bonvento, Gilles, Humbert, Sandrine, Saudou, Frédéric, Hantraye, Philippe, Mérienne, Karine, Bemelmans, Alexis-Pierre, Perrier, Anselme, Déglon, Nicole, Brouillet, Emmanuel, Service MIRCEN (MIRCEN), Université Paris-Saclay-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), Laboratoire des Maladies Neurodégénératives - UMR 9199 (LMN), 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), 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), Institut d'Imagerie BioMédicale (I2BM), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay, Biocortech, Service de Biologie Intégrative et Génétique Moléculaire (SBIGeM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM), inconnu, Inconnu, Grenoble Institut des Neurosciences (GIN), Université Joseph Fourier - Grenoble 1 (UJF)-Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de neurosciences cognitives et adaptatives (LNCA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Hôpital Ophtalmique Jules-Gonin [Lausanne], Université de Lausanne (UNIL)-Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Fondation FondaMental [Créteil], Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Généthon-Université d'Évry-Val-d'Essonne (UEVE), Régulations cellulaires et oncogenèse (RCO), Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Université Joseph Fourier - Grenoble 1 (UJF)-Institut National de la Santé et de la Recherche Médicale (INSERM), 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), Institut de Biologie du Développement de Marseille (IBDM), Aix Marseille Université (AMU)-Collège de France (CdF (institution))-Centre National de la Recherche Scientifique (CNRS), 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)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie François JACOB (JACOB), [GIN] Grenoble Institut des Neurosciences (GIN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Hospitalier Universitaire [Grenoble] (CHU), 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)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, ANR-11-INBS-0011,NeurATRIS,Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences(2011), European Project: 222925,EC:FP7:HEALTH,FP7-HEALTH-2007-B,NEUGENE(2008), Centre National de la Recherche Scientifique (CNRS)-Service MIRCEN (MIRCEN), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Grenoble Alpes (UGA), cambon, karine, Infrastructures - Infrastructure de Recherche Translationnelle pour les Biothérapies en Neurosciences - - NeurATRIS2011 - ANR-11-INBS-0011 - INBS - VALID, and Advanced gene therapy tools for treatment of CNS-specific disorders - NEUGENE - - EC:FP7:HEALTH2008-10-01 - 2012-03-31 - 222925 - VALID
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Male ,congenital, hereditary, and neonatal diseases and abnormalities ,Animals ,Cells, Cultured ,Corpus Striatum/enzymology ,Disease Models, Animal ,Down-Regulation/genetics ,Electron Transport Complex IV/metabolism ,Hand Strength/physiology ,Huntingtin Protein/genetics ,Huntington Disease/genetics ,Huntington Disease/therapy ,Macaca fascicularis ,Mice ,Mice, Inbred C57BL ,Mice, Transgenic ,Motor Activity ,Mutation/genetics ,Neurons/metabolism ,Phosphopyruvate Hydratase/metabolism ,Protein-Serine-Threonine Kinases/genetics ,Protein-Serine-Threonine Kinases/metabolism ,RNA, Small Interfering/genetics ,RNA, Small Interfering/metabolism ,Trans-Activators/genetics ,Trans-Activators/metabolism ,Transcription Factors/genetics ,Transcription Factors/metabolism ,Huntington ,kinase ,[SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,[SDV]Life Sciences [q-bio] ,Down-Regulation ,neurons ,Protein Serine-Threonine Kinases ,Electron Transport Complex IV ,Doublecortin-Like Kinases ,mental disorders ,[SDV.NEU] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,RNA, Small Interfering ,ComputingMilieux_MISCELLANEOUS ,Huntingtin Protein ,Hand Strength ,[SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology ,Original Articles ,Corpus Striatum ,Editor's Choice ,Huntington Disease ,nervous system ,Phosphopyruvate Hydratase ,Mutation ,Trans-Activators ,chromatin ,[SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC] ,transcription ,Transcription Factors - Abstract
Expression of the neuronal kinase DCLK3 is reduced in Huntington’s disease. Galvan et al. report that DCLK3 silencing in the mouse striatum exacerbates the toxicity of mutant huntingtin, whereas DCLK3 overexpression is neuroprotective, and show that DCLK3 regulates the expression of many genes involved in transcription regulation and chromatin remodelling., The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington’s disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington’s disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington’s disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington’s disease could render the striatum highly vulnerable to neurodegeneration.
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- 2018
10. Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease
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Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Jan, Caroline, Dufour, Noëlle, Hantraye, Philippe, Elalouf, Jean-Marc, De Chaldée, Michel, Déglon, Nicole, Brouillet, Emmanuel, Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Jan, Caroline, Dufour, Noëlle, Hantraye, Philippe, Elalouf, Jean-Marc, De Chaldée, Michel, Déglon, Nicole, and Brouillet, Emmanuel
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The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein µ-crystallin (Crym). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone (TH) T3 (3,5,3′-triiodo-l-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulfur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the THs deregulation reported in HD patients
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- 2017
11. Lentiviral Vectors in Huntington's Disease Research and Therapy.
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Delzor, Aurélie, Dufour, Noëlle, and Déglon, Nicole
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- 2014
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12. Allele-Specific Silencing of Mutant Huntingtin in Rodent Brain and Human Stem Cells.
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Drouet, Valérie, Ruiz, Marta, Zala, Diana, Feyeux, Maxime, Auregan, Gwennaëlle, Cambon, Karine, Troquier, Laetitia, Carpentier, Johann, Aubert, Sophie, Merienne, Nicolas, Bourgois-Rocha, Fany, Hassig, Raymonde, Rey, Maria, Dufour, Noëlle, Saudou, Frédéric, Perrier, Anselme L., Hantraye, Philippe, and Déglon, Nicole
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ALLELES ,HUNTINGTIN protein ,STEM cells ,LABORATORY rodents ,HUNTINGTON disease ,POLYGLUTAMINE ,RNA interference - Abstract
Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder resulting from polyglutamine expansion in the huntingtin (HTT) protein and for which there is no cure. Although suppression of both wild type and mutant HTT expression by RNA interference is a promising therapeutic strategy, a selective silencing of mutant HTT represents the safest approach preserving WT HTT expression and functions. We developed small hairpin RNAs (shRNAs) targeting single nucleotide polymorphisms (SNP) present in the HTT gene to selectively target the disease HTT isoform. Most of these shRNAs silenced, efficiently and selectively, mutant HTT in vitro. Lentiviral-mediated infection with the shRNAs led to selective degradation of mutant HTT mRNA and prevented the apparition of neuropathology in HD rat's striatum expressing mutant HTT containing the various SNPs. In transgenic BACHD mice, the mutant HTT allele was also silenced by this approach, further demonstrating the potential for allele-specific silencing. Finally, the allele-specific silencing of mutant HTT in human embryonic stem cells was accompanied by functional recovery of the vesicular transport of BDNF along microtubules. These findings provide evidence of the therapeutic potential of allele-specific RNA interference for HD. [ABSTRACT FROM AUTHOR]
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- 2014
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13. In vivo tau spreading relies on the transsynaptic transfer of soluble wild-type tau species
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Buee, Luc, Dujardin, Simon, Bégard, Séverine, Raphaëlle, Caillierez, Lécolle, Katia, Dufour, Noelle, Auregan, Gwenaelle, Winderickx, Joris, Philippe, Hantraye, Deglon, Nicole, and Colin, Morvane
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- 2013
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14. Sustained effects of nonallele-specific Huntingtin silencing.
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Drouet, Valérie, Perrin, Valérie, Hassig, Raymonde, Dufour, Noëlle, Auregan, Gwennaelle, Alves, Sandro, Bonvento, Gilles, Brouillet, Emmanuel, Luthi-Carter, Ruth, Hantraye, Philippe, and Déglon, Nicole
- Abstract
Objective Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin (htt) protein. No cure is available to date to alleviate neurodegeneration. Recent studies have demonstrated that RNA interference represents a promising approach for the treatment of autosomal dominant disorders. But whether an allele-specific silencing of mutant htt or a nonallele-specific silencing should be considered has not been addressed. Methods We developed small hairpin RNA targeting mutant or wild-type htt transcripts, or both. Results We confirmed the therapeutic potential of sihtt administered with lentiviral vectors in rodent models of HD and showed that initiation of small interfering RNA treatment after the onset of HD symptoms is still efficacious and reduces the HD-like pathology. We then addressed the question of the impact of nonallele-specific silencing and demonstrated that silencing of endogenous htt to 25 to 35% in vivo is altering several pathways associated with known htt functions but is not inducing overt toxicity or increasing striatal vulnerability up to 9 months after treatment. Interpretation These data indicate that the coincident silencing of the wild-type and mutant htt may be considered as a therapeutic tool for HD. Ann Neurol 2009;65:276-285 [ABSTRACT FROM AUTHOR]
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- 2009
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15. Normal Aging Modulates the Neurotoxicity of Mutant Huntingtin.
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Diguet, Elsa, Petit, Fanny, Escartin, Carole, Cambon, Karine, Bizat, Nicolas, Dufour, Noëlle, Hantraye, Philippe, Déglon, Nicole, and Brouillet, Emmanuel
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NEURODEGENERATION ,HUNTINGTON'S chorea treatment ,STEREOTAXIC techniques ,SURGICAL & topographical anatomy ,LABORATORY rats ,HISTOLOGICAL techniques ,CARCINOGENESIS ,GLUTAMINE synthetase ,STEREOENCEPHALOTOMY - Abstract
Aging likely plays a role in neurodegenerative disorders. In Huntington's disease (HD), a disorder caused by an abnormal expansion of a polyglutamine tract in the protein huntingtin (Htt), the role of aging is unclear. For a given tract length, the probability of disease onset increases with age. There are mainly two hypotheses that could explain adult onset in HD: Either mutant Htt progressively produces cumulative defects over time or ''normal'' aging renders neurons more vulnerable to mutant Htt toxicity. In the present study, we directly explored whether aging affected the toxicity of mutant Htt in vivo. We studied the impact of aging on the effects produced by overexpression of an N-terminal fragment of mutant Htt, of wild-type Htt or of a b-Galactosidase (b-Gal) reporter gene in the rat striatum. Stereotaxic injections of lentiviral vectors were performed simultaneously in young (3 week) and old (15 month) rats. Histological evaluation at different time points after infection demonstrated that the expression of mutant Htt led to pathological changes that were more severe in old rats, including an increase in the number of small Htt-containing aggregates in the neuropil, a greater loss of DARPP-32 immunoreactivity and striatal neurons as assessed by unbiased stereological counts. The present results support the hypothesis that ''normal'' aging is involved in HD pathogenesis, and suggest that age-related cellular defects might constitute potential therapeutic targets for HD. [ABSTRACT FROM AUTHOR]
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- 2009
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16. Allele-Specific RNA Silencing of Mutant Ataxin-3 Mediates Neuroprotection in a Rat Model of Machado-Joseph Disease.
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Alves, Sandro, Nascimento-Ferreira, Isabel, Auregan, Gwennaëlle, Hassig, Raymonde, Dufour, Noëlle, Brouillet, Emmanuel, de Lima, Maria C. Pedroso, Hantraye, Philippe, de Almeida, Luís Pereira, and Déglon, Nicole
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GENETIC research ,RNA ,NEUROSCIENCES ,POLYCYSTIC kidney disease ,GENETIC polymorphisms ,NUCLEOTIDES ,LABORATORY rats ,CENTRAL nervous system ,HUMAN abnormalities - Abstract
Recent studies have demonstrated that RNAi is a promising approach for treating autosomal dominant disorders. However, discrimination between wild-type and mutant transcripts is essential, to preserve wild-type expression and function. A single nucleotide polymorphism (SNP) is present in more than 70% of patients with Machado-Joseph disease (MJD). We investigated whether this SNP could be used to inactivate mutant ataxin-3 selectively. Lentiviral-mediated silencing of mutant human ataxin-3 was demonstrated in vitro and in a rat model of MJD in vivo. The allele-specific silencing of ataxin-3 significantly decreased the severity of the neuropathological abnormalities associated with MJD. These data demonstrate that RNAi has potential for use in MJD treatment and constitute the first proof-of-principle for allele-specific silencing in the central nervous system. [ABSTRACT FROM AUTHOR]
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- 2008
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17. Retinal cell type expression specificity of HIV-1-derived gene transfer vectors upon subretinal injection in the adult rat: influence of pseudotyping and promoter.
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Bemelmans, Alexis-Pierre, Bonnel, Sébastien, Houhou, Leïla, Dufour, Noëlle, Nandrot, Emeline, Helmlinger, Dominique, Sarkis, Chamsy, Abitbol, Marc, and Mallet, Jacques
- Abstract
Background Gene therapy, and particularly gene restoration, is currently a great hope for non-curable hereditary retinal degeneration. Clinical applications require a gene transfer vector capable of accurately targeting particular cell types in the retina. To develop such a vector, we compared the expression of a reporter gene after subretinal injections of lentiviral constructs of various pseudotypes and with the transgene expression driven by various promoters. Methods Lentiviral vectors expressing the green fluorescent protein (GFP) under the transcriptional control of cytomegalovirus (CMV), mouse phosphoglycerate kinase (PGK), human elongation factor 1-α (EF1α), or human rhodopsin (RHO) promoters were pseudotyped by vesicular stomatitis virus (VSV) or Mokola virus envelope proteins. These constructs were injected into the subretinal space of adult rdy rats. GFP expression was analyzed in vivo 1 and 4 weeks after injection by fundus examination. The precise location of transgene expression was then determined by immunohistochemistry and in situ hybridization. Results Constructs of both vesicular stomatitis virus and Mokola pseudotypes with ubiquitous promoters led to a strong expression of GFP in vivo. Histological studies confirmed the production of GFP in the retinal pigment epithelium (RPE) in most cases. However, only the combination of the VSV pseudotype with the RHO promoter led to GFP production in photoreceptors, and did so in a sporadic manner. Conclusions Mokola-pseudotyped lentiviral vectors are effective for specific gene transfer to the RPE. Neither VSV- nor Mokola-pseudotyped lentiviral vectors are adequate for efficient gene transfer to photoreceptors of adult rats. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]
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- 2005
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18. Grafts of Brain-Derived Neurotrophic Factor and Neurotrophin 3-Transduced Primate Schwann Cells Lead to Functional Recovery of the Demyelinated Mouse Spinal Cord.
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Girard, Christelle, Bemelmans, Alexis-Pierre, Dufour, Noëlle, Mallet, Jacques, Bachelin, Corinne, Nait-Oumesmar, Brahim, Baron-Van Evercooren, Anne, and Lachapelle, François
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MYELIN sheath ,CELL membranes ,LABORATORY mice ,LABORATORY animals ,HIV ,CYTOKINES ,CELL division ,NEUROSCIENCES - Abstract
Experimental studies provided overwhelming proof that transplants of myelin-forming cells achieve efficient remyelination in the CNS. Among cellular candidates, Schwann ceils can be used for autologous transplantation to ensure robust remyelination of lesions and to deliver therapeutic factors in the CNS. In the present study, macaque Schwann cells expressing green fluorescent protein (GFP) were infected with human immunodeficiency virus-derived vectors overexpressing brain-derived neurotrophic factor (BDNF) or Neurotrophin 3 (NT-3), two neurotrophins that also modulate glial cell biology. The ability of transgenic Schwann cells to secrete growth factors was assessed by ELISA and showed 35- and 62-fold increases in BDNF and NT-3, respectively, in transduced macaque Schwann cell supernatants. Conditioned media of BDNF- and NT-3-transduced Schwann cells reduced Schwann cell proliferation and favored their differentiation in vitro. Transgenic cells were grafted in demyelinated spinal cords of adult nude mice. Two behavioral assays showed that NT-3- and BDNF-transduced Schwann cells promoted faster and stronger functional recovery than GFP-transduced Schwann cells. Morphological analysis indicated that functional recovery correlated with enhanced proliferation and differentiation of resident oligodendrocyte progenitors and enhanced oligodendrocyte and Schwann cell differentiation. Moreover, NT-3-transduced Schwann cells provided neuroprotection and reduced astrogliosis. These results underline the potential therapeutic benefit of combining neuroprotection and activation of myelin-forming cells to restore altered functions in demyelinating diseases of the CNS. [ABSTRACT FROM AUTHOR]
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- 2005
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19. The C-Terminal Domain of LRRK2 with the G2019S Substitution Increases Mutant A53T α-Synuclein Toxicity in Dopaminergic Neurons In Vivo.
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Cresto, Noémie, Gardier, Camille, Gaillard, Marie-Claude, Gubinelli, Francesco, Roost, Pauline, Molina, Daniela, Josephine, Charlène, Dufour, Noëlle, Auregan, Gwenaëlle, Guillermier, Martine, Bernier, Suéva, Jan, Caroline, Gipchtein, Pauline, Hantraye, Philippe, Chartier-Harlin, Marie-Christine, Bonvento, Gilles, Van Camp, Nadja, Taymans, Jean-Marc, Cambon, Karine, and Liot, Géraldine
- Subjects
DARDARIN ,DOPAMINERGIC neurons ,PARKINSON'S disease ,NEURODEGENERATION ,BEHAVIORAL assessment - Abstract
Alpha-synuclein (α-syn) and leucine-rich repeat kinase 2 (LRRK2) play crucial roles in Parkinson's disease (PD). They may functionally interact to induce the degeneration of dopaminergic (DA) neurons via mechanisms that are not yet fully understood. We previously showed that the C-terminal portion of LRRK2 (ΔLRRK2) with the G2019S mutation (ΔLRRK2
G2019S ) was sufficient to induce neurodegeneration of DA neurons in vivo, suggesting that mutated LRRK2 induces neurotoxicity through mechanisms that are (i) independent of the N-terminal domains and (ii) "cell-autonomous". Here, we explored whether ΔLRRK2G2019S could modify α-syn toxicity through these two mechanisms. We used a co-transduction approach in rats with AAV vectors encoding ΔLRRK2G2019S or its "dead" kinase form, ΔLRRK2DK , and human α-syn with the A53T mutation (AAV-α-synA53T ). Behavioral and histological evaluations were performed at 6- and 15-weeks post-injection. Results showed that neither form of ΔLRRK2 alone induced the degeneration of neurons at these post-injection time points. By contrast, injection of AAV-α-synA53T alone resulted in motor signs and degeneration of DA neurons. Co-injection of AAV-α-synA53T with AAV-ΔLRRK2G2019S induced DA neuron degeneration that was significantly higher than that induced by AAV-α-synA53T alone or with AAV-ΔLRRK2DK . Thus, mutated α-syn neurotoxicity can be enhanced by the C-terminal domain of LRRK2G2019 alone, through cell-autonomous mechanisms. [ABSTRACT FROM AUTHOR]- Published
- 2021
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20. Loss of the thyroid hormone-binding protein Crym renders striatal neurons more vulnerable to mutant huntingtin in Huntington's disease
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Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Jan, Caroline, Dufour, Noëlle, Hantraye, Philippe, Elalouf, Jean-Marc, De Chaldée, Michel, Déglon, Nicole, Brouillet, Emmanuel, Francelle, Laetitia, Galvan, Laurie, Gaillard, Marie-Claude, Guillermier, Martine, Houitte, Diane, Bonvento, Gilles, Petit, Fanny, Jan, Caroline, Dufour, Noëlle, Hantraye, Philippe, Elalouf, Jean-Marc, De Chaldée, Michel, Déglon, Nicole, and Brouillet, Emmanuel
- Abstract
The mechanisms underlying preferential atrophy of the striatum in Huntington's disease (HD) are unknown. One hypothesis is that a set of gene products preferentially expressed in the striatum could determine the particular vulnerability of this brain region to mutant huntingtin (mHtt). Here, we studied the striatal protein µ-crystallin (Crym). Crym is the NADPH-dependent p38 cytosolic T3-binding protein (p38CTBP), a key regulator of thyroid hormone (TH) T3 (3,5,3′-triiodo-l-thyronine) transportation. It has been also recently identified as the enzyme that reduces the sulfur-containing cyclic ketimines, which are potential neurotransmitters. Here, we confirm the preferential expression of the Crym protein in the rodent and macaque striatum. Crym expression was found to be higher in the macaque caudate than in the putamen. Expression of Crym was reduced in the BACHD and Knock-in 140CAG mouse models of HD before onset of striatal atrophy. We show that overexpression of Crym in striatal medium-size spiny neurons using a lentiviral-based strategy in mice is neuroprotective against the neurotoxicity of an N-terminal fragment of mHtt in vivo. Thus, reduction of Crym expression in HD could render striatal neurons more susceptible to mHtt suggesting that Crym may be a key determinant of the vulnerability of the striatum. In addition our work points to Crym as a potential molecular link between striatal degeneration and the THs deregulation reported in HD patients
21. Lentiviral Delivery of the Human Wild-type Tau Protein Mediates a Slow and Progressive Neurodegenerative Tau Pathology in the Rat Brain.
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Caillierez, Raphaëlle, Bégard, Séverine, Lécolle, Katia, Deramecourt, Vincent, Zommer, Nadège, Dujardin, Simon, Loyens, Anne, Dufour, Noëlle, Aurégan, Gwennaëlle, Winderickx, Joris, Hantraye, Philippe, Déglon, Nicole, Buée, Luc, and Colin, Morvane
- Subjects
- *
LENTIVIRUSES , *RETROVIRUSES , *TAU proteins , *TUBULINS , *LABORATORY rats - Abstract
Most models for tauopathy use a mutated form of the Tau gene, MAPT, that is found in frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) and that leads to rapid neurofibrillary degeneration (NFD). Use of a wild-type (WT) form of human Tau protein to model the aggregation and associated neurodegenerative processes of Tau in the mouse brain has thus far been unsuccessful. In the present study, we generated an original 'sporadic tauopathy-like' model in the rat hippocampus, encoding six Tau isoforms as found in humans, using lentiviral vectors (LVs) for the delivery of a human WT Tau. The overexpression of human WT Tau in pyramidal neurons resulted in NFD, the morphological characteristics and kinetics of which reflected the slow and sporadic neurodegenerative processes observed in sporadic tauopathies, unlike the rapid neurodegenerative processes leading to cell death and ghost tangles triggered by the FTDP-17 mutant Tau P301L. This new model highlights differences in the molecular and cellular mechanisms underlying the pathological processes induced by WT and mutant Tau and suggests that preference should be given to animal models using WT Tau in the quest to understand sporadic tauopathies. [ABSTRACT FROM AUTHOR]
- Published
- 2013
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22. Effect of Chronic Treatment with Riluzole on the Nigrostriatal Dopaminergic System in Weaver Mutant Mice
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Douhou, Aıcha, Debeir, Thomas, Murer, Mario Gustavo, Do, Louis, Dufour, Noëlle, Blanchard, Véronique, Moussaoui, Saliha, Bohme, Georg Andrees, Agid, Yves, and Raisman-Vozari, Rita
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- *
DOPAMINERGIC neurons , *NEUROPLASTICITY - Abstract
The effects of a chronic treatment with the anti-glutamate and sodium channel modulating neuroprotective agent riluzole on the degeneration of dopamine-containing neurons were studied in the brain of weaver mutant mice. In these animals, as in Parkinson''s disease, dopaminergic neurons of the nigro-striatal pathway undergo spontaneous and progressive cell death. Homozygous weaver mice were orally treated twice a day with either 8 mg/kg riluzole or placebo for 2 months. Quantification of tyrosine-hydroxylase and dopamine-transporter axonal immunostaining in the striatum revealed that riluzole significantly increased the density of striatal dopaminergic nerve terminals. These results suggest that riluzole protects dopaminergic processes in the weaver mice and/or promotes their neuroplasticity. [Copyright &y& Elsevier]
- Published
- 2002
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23. The C-terminal domain of LRRK2 with the G2019S mutation is sufficient to produce neurodegeneration of dopaminergic neurons in vivo.
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Cresto, Noémie, Gaillard, Marie-Claude, Gardier, Camille, Gubinelli, Francesco, Diguet, Elsa, Bellet, Déborah, Legroux, Laurine, Mitja, Julien, Auregan, Gwenaëlle, Guillermier, Martine, Josephine, Charlène, Jan, Caroline, Dufour, Noëlle, Joliot, Alain, Hantraye, Philippe, Bonvento, Gilles, Déglon, Nicole, Bemelmans, Alexis-Pierre, Cambon, Karine, and Liot, Géraldine
- Subjects
- *
DOPAMINERGIC neurons , *DARDARIN , *MONOAMINE transporters , *PARKINSON'S disease , *SUBSTANTIA nigra , *NEURODEGENERATION , *DOPAMINE analysis , *CELL death - Abstract
The G2019S substitution in the kinase domain of LRRK2 (LRRK2G2019S) is the most prevalent mutation associated with Parkinson's disease (PD). Neurotoxic effects of LRRK2G2019S are thought to result from an increase in its kinase activity as compared to wild type LRRK2. However, it is unclear whether the kinase domain of LRRK2G2019S is sufficient to trigger degeneration or if the full length protein is required. To address this question, we generated constructs corresponding to the C-terminal domain of LRRK2 (ΔLRRK2). A kinase activity that was increased by G2019➔S substitution could be detected in ΔLRRK2. However biochemical experiments suggested it did not bind or phosphorylate the substrate RAB10, in contrast to full length LRRK2. The overexpression of ΔLRRK2G2019S in the rat striatum using lentiviral vectors (LVs) offered a straightforward and simple way to investigate its effects in neurons in vivo. Results from a RT-qPCR array analysis indicated that ΔLRRK2G2019S led to significant mRNA expression changes consistent with a kinase-dependent mechanism. We next asked whether ΔLRRK2 could be sufficient to trigger neurodegeneration in the substantia nigra pars compacta (SNc) in adult rats. Six months after infection of the substantia nigra pars compacta (SNc) with LV-ΔLRRK2WT or LV-ΔLRRK2G2019S, the number of DA neurons was unchanged. To examine whether higher levels of ΔLRRK2G2019S could trigger degeneration we cloned ΔLRRK2 in AAV2/9 construct. As expected, AAV2/9 injected in the SNc led to neuronal expression of ΔLRRK2WT and ΔLRRK2G2019S at much higher levels than those obtained with LVs. Six months after injection, unbiased stereology showed that AAV-ΔLRRK2G2019S produced a significant ~30% loss of neurons positive for tyrosine hydroxylase- and for the vesicular dopamine transporter whereas AAV-ΔLRRK2WT did not. These findings show that overexpression of the C-terminal part of LRRK2 containing the mutant kinase domain is sufficient to trigger degeneration of DA neurons, through cell-autonomous mechanisms, possibly independent of RAB10. • New LVs and AAVs were developed to study the effects of a C-terminal fragment of LRRK2 containing the kinase domain. • ΔLRRK2G2019S produces molecular and cellular effects that are kinase activity-dependent. • In vivo, ΔLRRK2G2019S leads to DA neurodegeneration when using AAV-mediated gene transfer. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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24. Reactive astrocytes promote proteostasis in Huntington's disease through the JAK2-STAT3 pathway.
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Abjean L, Ben Haim L, Riquelme-Perez M, Gipchtein P, Derbois C, Palomares MA, Petit F, Hérard AS, Gaillard MC, Guillermier M, Gaudin-Guérif M, Aurégan G, Sagar N, Héry C, Dufour N, Robil N, Kabani M, Melki R, De la Grange P, Bemelmans AP, Bonvento G, Deleuze JF, Hantraye P, Flament J, Bonnet E, Brohard S, Olaso R, Brouillet E, Carrillo-de Sauvage MA, and Escartin C
- Subjects
- Animals, Mice, Astrocytes metabolism, Proteostasis, Neurons metabolism, Huntingtin Protein genetics, Huntingtin Protein metabolism, Huntington Disease genetics, Neurodegenerative Diseases pathology
- Abstract
Huntington's disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntington's disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntington's disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntington's disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntington's disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntington's disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
- Published
- 2023
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25. The striatal kinase DCLK3 produces neuroprotection against mutant huntingtin.
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Galvan L, Francelle L, Gaillard MC, de Longprez L, Carrillo-de Sauvage MA, Liot G, Cambon K, Stimmer L, Luccantoni S, Flament J, Valette J, de Chaldée M, Auregan G, Guillermier M, Joséphine C, Petit F, Jan C, Jarrige M, Dufour N, Bonvento G, Humbert S, Saudou F, Hantraye P, Merienne K, Bemelmans AP, Perrier AL, Déglon N, and Brouillet E
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Doublecortin-Like Kinases, Down-Regulation genetics, Electron Transport Complex IV metabolism, Hand Strength physiology, Huntington Disease genetics, Macaca fascicularis, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Motor Activity, Neurons metabolism, Phosphopyruvate Hydratase metabolism, Protein Serine-Threonine Kinases genetics, RNA, Small Interfering genetics, RNA, Small Interfering metabolism, Trans-Activators genetics, Trans-Activators metabolism, Transcription Factors genetics, Transcription Factors metabolism, Corpus Striatum enzymology, Huntingtin Protein genetics, Huntington Disease therapy, Mutation genetics, Protein Serine-Threonine Kinases metabolism
- Abstract
The neurobiological functions of a number of kinases expressed in the brain are unknown. Here, we report new findings on DCLK3 (doublecortin like kinase 3), which is preferentially expressed in neurons in the striatum and dentate gyrus. Its function has never been investigated. DCLK3 expression is markedly reduced in Huntington's disease. Recent data obtained in studies related to cancer suggest DCLK3 could have an anti-apoptotic effect. Thus, we hypothesized that early loss of DCLK3 in Huntington's disease may render striatal neurons more susceptible to mutant huntingtin (mHtt). We discovered that DCLK3 silencing in the striatum of mice exacerbated the toxicity of an N-terminal fragment of mHtt. Conversely, overexpression of DCLK3 reduced neurodegeneration produced by mHtt. DCLK3 also produced beneficial effects on motor symptoms in a knock-in mouse model of Huntington's disease. Using different mutants of DCLK3, we found that the kinase activity of the protein plays a key role in neuroprotection. To investigate the potential mechanisms underlying DCLK3 effects, we studied the transcriptional changes produced by the kinase domain in human striatal neurons in culture. Results show that DCLK3 regulates in a kinase-dependent manner the expression of many genes involved in transcription regulation and nucleosome/chromatin remodelling. Consistent with this, histological evaluation showed DCLK3 is present in the nucleus of striatal neurons and, protein-protein interaction experiments suggested that the kinase domain interacts with zinc finger proteins, including the transcriptional activator adaptor TADA3, a core component of the Spt-ada-Gcn5 acetyltransferase (SAGA) complex which links histone acetylation to the transcription machinery. Our novel findings suggest that the presence of DCLK3 in striatal neurons may play a key role in transcription regulation and chromatin remodelling in these brain cells, and show that reduced expression of the kinase in Huntington's disease could render the striatum highly vulnerable to neurodegeneration.
- Published
- 2018
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26. Striatal long noncoding RNA Abhd11os is neuroprotective against an N-terminal fragment of mutant huntingtin in vivo.
- Author
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Francelle L, Galvan L, Gaillard MC, Petit F, Bernay B, Guillermier M, Bonvento G, Dufour N, Elalouf JM, Hantraye P, Déglon N, de Chaldée M, and Brouillet E
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Female, Humans, Huntingtin Protein, Huntington Disease metabolism, Male, Mice, Inbred C57BL, RNA, Small Interfering genetics, RNA, Untranslated metabolism, Reverse Transcriptase Polymerase Chain Reaction, Serine Proteases metabolism, Corpus Striatum metabolism, Down-Regulation genetics, Gene Expression genetics, Gene Expression Regulation genetics, Huntington Disease genetics, Mutation, Nerve Tissue Proteins genetics, Neuroprotective Agents, Nuclear Proteins genetics, RNA, Untranslated genetics, Serine Proteases genetics
- Abstract
A large number of gene products that are enriched in the striatum have ill-defined functions, although they may have key roles in age-dependent neurodegenerative diseases affecting the striatum, especially Huntington disease (HD). In the present study, we focused on Abhd11os, (called ABHD11-AS1 in human) which is a putative long noncoding RNA (lncRNA) whose expression is enriched in the mouse striatum. We confirm that despite the presence of 2 small open reading frames (ORFs) in its sequence, Abhd11os is not translated into a detectable peptide in living cells. We demonstrate that Abhd11os levels are markedly reduced in different mouse models of HD. We performed in vivo experiments in mice using lentiviral vectors encoding either Abhd11os or a small hairpin RNA targeting Abhd11os. Results show that Abhd11os overexpression produces neuroprotection against an N-terminal fragment of mutant huntingtin, whereas Abhd11os knockdown is protoxic. These novel results indicate that the loss lncRNA Abhd11os likely contribute to striatal vulnerability in HD. Our study emphasizes that lncRNA may play crucial roles in neurodegenerative diseases., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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27. Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies.
- Author
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Dujardin S, Lécolle K, Caillierez R, Bégard S, Zommer N, Lachaud C, Carrier S, Dufour N, Aurégan G, Winderickx J, Hantraye P, Déglon N, Colin M, and Buée L
- Subjects
- Animals, Brain pathology, Cell Differentiation genetics, Cells, Cultured, Disease Models, Animal, Disease Progression, Embryo, Mammalian, Gene Transfer Techniques, Humans, Microfluidic Analytical Techniques, Microscopy, Confocal, Microtubule-Associated Proteins genetics, Microtubule-Associated Proteins metabolism, Mutation genetics, Protein Transport physiology, RNA, Messenger metabolism, Rats, Rats, Wistar, Neurons metabolism, Tauopathies pathology, tau Proteins metabolism
- Abstract
Background: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau., Results: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild-type one., Conclusion: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading.
- Published
- 2014
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