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

BMC Genomics. 2012 Mar 13;13:91. doi: 10.1186/1471-2164-13-91.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caenorhabditis elegans / genetics*
  • Cell Survival / genetics
  • Corpus Striatum / metabolism
  • Genome-Wide Association Study
  • High-Throughput Screening Assays
  • Huntingtin Protein
  • Metabolic Networks and Pathways / genetics
  • Mice
  • Mice, Transgenic
  • Molecular Sequence Annotation
  • Mutation*
  • Nerve Tissue Proteins / genetics*
  • Neurodegenerative Diseases / genetics
  • Neurons / metabolism*
  • Peptides / genetics*
  • RNA Interference*
  • RNA Replicase / genetics

Substances

  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Peptides
  • polyglutamine
  • RNA Replicase
  • RNA-directed RNA polymerase RRF-3, C elegans