A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
Year: 2012
Type: article
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.
Source: PLoS Genetics
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $3,043
Awards: G1895557780, Triplet Repeat Disease:Requirement for Caspase Cleavage, Huntingtin interacting proteins as modifiers of Huntington's disease, Multidisciplinary Training in Brain Disorders and Development, G3549828030, Probing Neurodegeneration with Drosophila, G418095673, G4615953562, G4868433279, Basic Mechanisms in Aging and Age Related Disease, G5520316217, G5950577451, G6638344749, National Center for Biomedical Ontology, G7854747882, Informatic Profiling of Clinically Relevant Mutation, Probing Neurodegeneration with Drosophila, G9000014473, G9000152989, Training in Basic Research on Aging and Age-Related Disease
OpenAlex ID: W2086431203