1. Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons
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Jean-Philippe Vert, Cédric Bicep, Rafael P. Vázquez-Manrique, Cendrine Tourette, J. Alex Parker, Frédéric Parmentier, François-Xavier Lejeune, Christian Neri, Lilia Mesrob, Institut de psychiatrie et neurosciences (U894 / UMS 1266), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche du Centre Hospitalier de l’Université de Montréal (CR CHUM), Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM)-Université de Montréal (UdeM), Centre de Bioinformatique (CBIO), MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL), Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, Institut Curie [Paris]-MINES ParisTech - École nationale supérieure des mines de Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM), Buck Institute, J.A.P. was supported by a Young Researcher Award from Inserm. R.V. is supported by a Poste Vert fellowship from Inserm. This work was supported by Inserm, the Agence Nationale de la Recherche (ANR), the Fondation pour la Recherche Médicale (FRM), Paris, France, the Hereditary Disease Foundation (USA) and the European Huntington Disease Network (Euro-HD, Germany)., BMC, Ed., Mines Paris - PSL (École nationale supérieure des mines de Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Psychiatrie et Neurosciences ( CPN - U894 ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Centre d'excellence en neuromique ( CRCHUM ), Université de Montréal-Hopital Notre-Dame, Centre de Bioinformatique ( CBIO ), MINES ParisTech - École nationale supérieure des mines de Paris-PSL Research University ( PSL ), Cancer et génôme: Bioinformatique, biostatistiques et épidémiologie d'un système complexe, and MINES ParisTech - École nationale supérieure des mines de Paris-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -INSTITUT CURIE
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Huntingtin ,lcsh:QH426-470 ,Cell Survival ,Transgene ,lcsh:Biotechnology ,Mice, Transgenic ,Nerve Tissue Proteins ,Neuroprotection ,Mice ,03 medical and health sciences ,0302 clinical medicine ,RNA interference ,[SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,lcsh:TP248.13-248.65 ,Genetics ,medicine ,Huntingtin Protein ,Animals ,Caenorhabditis elegans ,030304 developmental biology ,Neurons ,0303 health sciences ,biology ,Neurotoxicity ,Molecular Sequence Annotation ,Neurodegenerative Diseases ,RNA-Dependent RNA Polymerase ,biology.organism_classification ,medicine.disease ,Corpus Striatum ,High-Throughput Screening Assays ,lcsh:Genetics ,medicine.anatomical_structure ,[ SDV.BBM.GTP ] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,Mutation ,[SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN] ,RNA Interference ,Neuron ,Peptides ,Neuroscience ,Metabolic Networks and Pathways ,030217 neurology & neurosurgery ,Genome-Wide Association Study ,Research Article ,Biotechnology - Abstract
Background A central goal in Huntington's disease (HD) research is to identify and prioritize candidate targets for neuroprotective intervention, which requires genome-scale information on the modifiers of early-stage neuron injury in HD. Results Here, we performed a large-scale RNA interference screen in C. elegans strains that express N-terminal huntingtin (htt) in touch receptor neurons. These neurons control the response to light touch. Their function is strongly impaired by expanded polyglutamines (128Q) as shown by the nearly complete loss of touch response in adult animals, providing an in vivo model in which to manipulate the early phases of expanded-polyQ neurotoxicity. In total, 6034 genes were examined, revealing 662 gene inactivations that either reduce or aggravate defective touch response in 128Q animals. Several genes were previously implicated in HD or neurodegenerative disease, suggesting that this screen has effectively identified candidate targets for HD. Network-based analysis emphasized a subset of high-confidence modifier genes in pathways of interest in HD including metabolic, neurodevelopmental and pro-survival pathways. Finally, 49 modifiers of 128Q-neuron dysfunction that are dysregulated in the striatum of either R/2 or CHL2 HD mice, or both, were identified. Conclusions Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.
- Published
- 2012
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