Abstract
BackgroundA 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.ResultsHere, 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.ConclusionsCollectively, these results highlight the relevance to HD pathogenesis, providing novel information on the potential therapeutic targets for neuroprotection in HD.
Highlights
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
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]
Since our screen was based on the manual quantification of touch response in 70-90 animals/RNA interference (RNAi) clone, which is considerably more labour-intensive and timeconsuming compared to faster RNAi screens such as those looking for modifiers of mutant htt aggregation [38,39], we evaluated whether the modifiers of 128Q
Summary
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. By targeting polyQ expression to C. elegans touch cells, we previously generated a model that recapitulates an early phase of expanded polyQ neurotoxicity, namely neuronal dysfunction in the absence of cell death [13,14] In these animals, exon 1 like htt fused to CFP was expressed in touch receptor neurons under the control of the promoter for the mec-3 gene (mec-3p) [14]. The loss of touch response in expanded-polyQ nematodes can be manipulated by genetic means, as exemplified by the protective effect of sirtuin overexpression and aggravating effect of loss-of-function in the sir-2.1/SIRT1–daf-16/FOXO cell survival pathway [14] These animals provide an in vivo model in which to screen for modifiers of neuron dysfunction induced by expanded polyQs. Here, we used 128Q nematodes in a large-scale functional RNA interference (RNAi) screen for modulation of response to touch.
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
