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A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease

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 mitochondri...

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Autores principales: Miller, John P., Yates, Bridget E., Al-Ramahi, Ismael, Berman, Ari E., Sanhueza, Mario, Kim, Eugene, de Haro, Maria, DeGiacomo, Francesco, Torcassi, Cameron, Holcomb, Jennifer, Gafni, Juliette, Mooney, Sean D., Botas, Juan, Ellerby, Lisa M., Hughes, Robert E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2012
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510027/
https://www.ncbi.nlm.nih.gov/pubmed/23209424
http://dx.doi.org/10.1371/journal.pgen.1003042
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author Miller, John P.
Yates, Bridget E.
Al-Ramahi, Ismael
Berman, Ari E.
Sanhueza, Mario
Kim, Eugene
de Haro, Maria
DeGiacomo, Francesco
Torcassi, Cameron
Holcomb, Jennifer
Gafni, Juliette
Mooney, Sean D.
Botas, Juan
Ellerby, Lisa M.
Hughes, Robert E.
author_facet Miller, John P.
Yates, Bridget E.
Al-Ramahi, Ismael
Berman, Ari E.
Sanhueza, Mario
Kim, Eugene
de Haro, Maria
DeGiacomo, Francesco
Torcassi, Cameron
Holcomb, Jennifer
Gafni, Juliette
Mooney, Sean D.
Botas, Juan
Ellerby, Lisa M.
Hughes, Robert E.
author_sort Miller, John P.
collection PubMed
description 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.
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spelling pubmed-35100272012-12-03 A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease Miller, John P. Yates, Bridget E. Al-Ramahi, Ismael Berman, Ari E. Sanhueza, Mario Kim, Eugene de Haro, Maria DeGiacomo, Francesco Torcassi, Cameron Holcomb, Jennifer Gafni, Juliette Mooney, Sean D. Botas, Juan Ellerby, Lisa M. Hughes, Robert E. PLoS Genet Research Article 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. Public Library of Science 2012-11-29 /pmc/articles/PMC3510027/ /pubmed/23209424 http://dx.doi.org/10.1371/journal.pgen.1003042 Text en © 2012 Miller et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Miller, John P.
Yates, Bridget E.
Al-Ramahi, Ismael
Berman, Ari E.
Sanhueza, Mario
Kim, Eugene
de Haro, Maria
DeGiacomo, Francesco
Torcassi, Cameron
Holcomb, Jennifer
Gafni, Juliette
Mooney, Sean D.
Botas, Juan
Ellerby, Lisa M.
Hughes, Robert E.
A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title_full A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title_fullStr A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title_full_unstemmed A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title_short A Genome-Scale RNA–Interference Screen Identifies RRAS Signaling as a Pathologic Feature of Huntington's Disease
title_sort genome-scale rna–interference screen identifies rras signaling as a pathologic feature of huntington's disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3510027/
https://www.ncbi.nlm.nih.gov/pubmed/23209424
http://dx.doi.org/10.1371/journal.pgen.1003042
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