title: A genome-scale RNA-interference screen identifies RRAS signaling as a pathologic feature of Huntington's disease.
abstract: 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.
authors.affiliation: The Buck Institute for Research on Aging, Novato, California, United States of America.
authors.forename: John P
authors.initials: JP
authors.lastname: Miller
authors.forename: Bridget E
authors.initials: BE
authors.lastname: Yates
authors.forename: Ismael
authors.initials: I
authors.lastname: Al-Ramahi
authors.forename: Ari E
authors.initials: AE
authors.lastname: Berman
authors.forename: Mario
authors.initials: M
authors.lastname: Sanhueza
authors.forename: Eugene
authors.initials: E
authors.lastname: Kim
authors.forename: Maria
authors.initials: M
authors.lastname: de Haro
authors.forename: Francesco
authors.initials: F
authors.lastname: DeGiacomo
authors.forename: Cameron
authors.initials: C
authors.lastname: Torcassi
authors.forename: Jennifer
authors.initials: J
authors.lastname: Holcomb
authors.forename: Juliette
authors.initials: J
authors.lastname: Gafni
authors.forename: Sean D
authors.initials: SD
authors.lastname: Mooney
authors.forename: Juan
authors.initials: J
authors.lastname: Botas
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ellerby
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hughes
mesh_terms: D000818:Animals; D003342:Corpus Striatum / Q000648:ultrastructure; D004195:Disease Models, Animal; D004331:Drosophila melanogaster / Q000235:genetics; D051231:Farnesyltranstransferase / Q000037:antagonists & inhibitors / Q000378:metabolism; D015894:Genome, Human; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000633:toxicity / Q000648:ultrastructure; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000494:pharmacology; D018631:ras Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: C505707:2-(2-furanyl)-7-phenyl(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D014230:Triazoles; D051231:Farnesyltranstransferase; C085929:RRAS protein, human; D018631:ras Proteins