Lejeune et al. BMC Genomics 2012, 13:91 http://www.biomedcentral.com/1471-2164/13/91 R E S E A R C H A R T I C L E Open Access Large-scale functional RNAi screen in C. elegans identifies genes that regulate the dysfunction of mutant polyglutamine neurons François-Xavier Lejeune1†, Lilia Mesrob1†, Frédéric Parmentier1†, Cedric Bicep1,2, Rafael P Vazquez-Manrique1,2, J Alex Parker1,2,3, Jean-Philippe Vert4,5,6, Cendrine Tourette1,2,7 and Christian Neri1,2* 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. Background Huntington’s disease (HD) is a dominantly-inherited dis- order caused by expanded polyglutamine (polyQ) tracts in the N-terminal portion of huntingtin (htt) and char- acterized by striatal and cortical degeneration [1]. While HD pathogenesis might involve a gain of toxic proper- ties by mutant htt as well as a loss of normal htt func- tion, several studies have emphasized a critical role of misfolded N-terminal fragments of mutant htt [2,3] that are natural products of htt processing [4]. Huntingtin is thought to have a large number of partner proteins involved in a variety of biological processes [5-8], sug- gesting that polyglutamine expansion in htt may alter * Correspondence: christian.neri@inserm.fr † Contributed equally 1INSERM, Unit 894, Laboratory of Neuronal Cell Biology and Pathology, 75014 Paris, France Full list of author information is available at the end of the article several biological processes that are essential to cellular homeostasis and neuron survival. Consistent with this possibility, transcriptomic analyses have revealed that mutant/polyQ-expanded htt expression may change the expression of a large number of genes in the caudate nucleus of HD subjects [9] and in the brain of fragment, knock-in and full-length mouse models of HD [10]. Given the complexity of alterations in cells and tissues expressing expanded polyQ/htt, gene perturbation screens are expected to shed light on the mechanisms that may be critical for cell response to mutant polyQ expression. Additionally, the integration of gene pertur- bation data with other types of ‘omics data such as for example gene expression profiles in HD mice [10] might fulfill the need for target profiling and prioritisation in HD. This may be particularly important when compar- ing target gene activity for the regulation of neuronal dysfunction versus that of neuronal death. Before the © 2012 Lejeune et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.