A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease

PLoS Genet. 2012;8(11):e1003042. doi: 10.1371/journal.pgen.1003042. Epub 2012 Nov 29.


A genome-scale RNAi screen was performed in a mammalian cell-based assay to identify modifiers of mutant huntingtin toxicity. Ontology analysis of suppressor data identified processes previously implicated in Huntington's disease, including proteolysis, glutamate excitotoxicity, and mitochondrial dysfunction. In addition to established mechanisms, the screen identified multiple components of the RRAS signaling pathway as loss-of-function suppressors of mutant huntingtin toxicity in human and mouse cell models. Loss-of-function in orthologous RRAS pathway members also suppressed motor dysfunction in a Drosophila model of Huntington's disease. Abnormal activation of RRAS and a down-stream effector, RAF1, was observed in cellular models and a mouse model of Huntington's disease. We also observe co-localization of RRAS and mutant huntingtin in cells and in mouse striatum, suggesting that activation of R-Ras may occur through protein interaction. These data indicate that mutant huntingtin exerts a pathogenic effect on this pathway that can be corrected at multiple intervention points including RRAS, FNTA/B, PIN1, and PLK1. Consistent with these results, chemical inhibition of farnesyltransferase can also suppress mutant huntingtin toxicity. These data suggest that pharmacological inhibition of RRAS signaling may confer therapeutic benefit in Huntington's disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / ultrastructure
  • Disease Models, Animal
  • Drosophila melanogaster / genetics
  • Farnesyltranstransferase / antagonists & inhibitors
  • Farnesyltranstransferase / metabolism
  • Genome, Human
  • HEK293 Cells
  • Humans
  • Huntingtin Protein
  • Huntington Disease* / genetics
  • Huntington Disease* / metabolism
  • Metabolic Networks and Pathways
  • Mice
  • Mitochondria / genetics
  • Mitochondria / metabolism
  • Mutation
  • Nerve Tissue Proteins* / genetics
  • Nerve Tissue Proteins* / toxicity
  • Nerve Tissue Proteins* / ultrastructure
  • Neurons / drug effects
  • Neurons / metabolism
  • Pyrimidines / pharmacology
  • RNA Interference*
  • Signal Transduction / drug effects
  • Triazoles / pharmacology
  • ras Proteins* / antagonists & inhibitors
  • ras Proteins* / genetics
  • ras Proteins* / metabolism


  • 2-(2-furanyl)-7-phenyl(1,2,4)triazolo(1,5-c)pyrimidin-5-amine
  • HTT protein, human
  • Huntingtin Protein
  • Nerve Tissue Proteins
  • Pyrimidines
  • Triazoles
  • Farnesyltranstransferase
  • RRAS protein, human
  • ras Proteins