Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons
<p>Abstract</p> <p>Background</p> <p>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.&...
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| Format: | Article |
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BMC
2012-03-01
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| Series: | BMC Genomics |
| Online Access: | http://www.biomedcentral.com/1471-2164/13/91 |
| _version_ | 1818927524132945920 |
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| author | Lejeune François-Xavier Mesrob Lilia Parmentier Frédéric Bicep Cedric Vazquez-Manrique Rafael P Parker J Alex Vert Jean-Philippe Tourette Cendrine Neri Christian |
| author_facet | Lejeune François-Xavier Mesrob Lilia Parmentier Frédéric Bicep Cedric Vazquez-Manrique Rafael P Parker J Alex Vert Jean-Philippe Tourette Cendrine Neri Christian |
| author_sort | Lejeune François-Xavier |
| collection | DOAJ |
| description | <p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Here, we performed a large-scale RNA interference screen in <it>C. elegans </it>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 <it>in vivo </it>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.</p> <p>Conclusions</p> <p>Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.</p> |
| first_indexed | 2024-12-20T03:14:23Z |
| format | Article |
| id | doaj.art-8e1268600d9a4ec7ac28c72c03f0bb18 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-20T03:14:23Z |
| publishDate | 2012-03-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-8e1268600d9a4ec7ac28c72c03f0bb182022-12-21T19:55:22ZengBMCBMC Genomics1471-21642012-03-011319110.1186/1471-2164-13-91Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neuronsLejeune François-XavierMesrob LiliaParmentier FrédéricBicep CedricVazquez-Manrique Rafael PParker J AlexVert Jean-PhilippeTourette CendrineNeri Christian<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>Here, we performed a large-scale RNA interference screen in <it>C. elegans </it>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 <it>in vivo </it>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.</p> <p>Conclusions</p> <p>Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.</p>http://www.biomedcentral.com/1471-2164/13/91 |
| spellingShingle | Lejeune François-Xavier Mesrob Lilia Parmentier Frédéric Bicep Cedric Vazquez-Manrique Rafael P Parker J Alex Vert Jean-Philippe Tourette Cendrine Neri Christian Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons BMC Genomics |
| title | Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| title_full | Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| title_fullStr | Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| title_full_unstemmed | Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| title_short | Large-scale functional RNAi screen in <it>C. elegans </it>identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| title_sort | large scale functional rnai screen in it c elegans it identifies genes that regulate the dysfunction of mutant polyglutamine neurons |
| url | http://www.biomedcentral.com/1471-2164/13/91 |
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