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

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.Huntington's disease (HD) is a dominantly-inherited disorder caused by expanded polyglutamine (polyQ) tracts in the N-terminal portion of huntingtin (htt) and characterized by striatal and cortical degeneration [1]. While HD pathogenesis might involve a gain of toxic properties by mutant htt as well as a loss of normal htt function, 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], suggesting that polyglutamine expansion in htt may alter several biological processes that are essential to cellular homeostasis and neuron survival. Consistent with this pos