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Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

ABSTRACT: 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.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.Collectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.

SUBMITTER: Lejeune FX

PROVIDER: S-EPMC3331833 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

Lejeune François-Xavier FX Mesrob Lilia L Parmentier Frédéric F Bicep Cedric C Vazquez-Manrique Rafael P RP Parker J Alex JA Vert Jean-Philippe JP Tourette Cendrine C Neri Christian C

BMC genomics 20120313

<h4>Background</h4>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.<h4>Results</h4>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 e ...[more]

PMID: 22413862

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Project description:Neuronal circuit development and function require proper synapse formation and maintenance. Genetic screens are one powerful method to identify the mechanisms shaping synaptic development and stability. However, genes with essential roles in non-neural tissues may be missed in traditional loss-of-function screens. In an effort to circumvent this limitation, we used neuron-specific RNAi knock down in Drosophila and assayed the formation, growth, and maintenance of the neuromuscular junction (NMJ). We examined 1970 Drosophila genes, each of which has a conserved ortholog in mammalian genomes. Knock down of 158 genes in post-mitotic neurons led to abnormalities in the neuromuscular system, including misapposition of active zone components opposite postsynaptic glutamate receptors, synaptic terminal overgrowth and undergrowth, abnormal accumulation of synaptic material within the axon, and retraction of synaptic terminals from their postsynaptic targets. Bioinformatics analysis demonstrates that genes with overlapping annotated function are enriched within the hits for each phenotype, suggesting that the shared biological function is important for that aspect of synaptic development. For example, genes for proteasome subunits and mitotic spindle organizers are enriched among the genes whose knock down leads to defects in synaptic apposition and NMJ stability. Such genes play essential roles in all cells, however the use of tissue- and temporally-restricted RNAi indicates that the proteasome and mitotic spindle organizers participate in discrete aspects of synaptic development. In addition to identifying functional classes of genes shaping synaptic development, this screen also identifies candidate genes whose role at the synapse can be validated by traditional loss-of-function analysis. We present one such example, the dynein-interacting protein NudE, and demonstrate that it is required for proper axonal transport and synaptic maintenance. Thus, this screen has identified both functional classes of genes as well as individual candidate genes that are critical for synaptic development and will be a useful resource for subsequent mechanistic analysis of synapse formation and maintenance.

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Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

Publications

Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons.

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