| Literature DB >> 23719381 |
Jeehye Park1,2,3, Ismael Al-Ramahi1,2, Qiumin Tan1,2,3, Nissa Mollema4,5, Javier R Diaz-Garcia1,2, Tatiana Gallego-Flores1,2, Hsiang-Chih Lu2,6, Sarita Lagalwar4,5, Lisa Duvick4,5, Hyojin Kang1,2, Yoontae Lee1,2,3, Paymaan Jafar-Nejad1,2, Layal S Sayegh1,2, Ronald Richman1,2,3, Xiuyun Liu1,2,3, Yan Gao1,2, Chad A Shaw1, J Simon C Arthur7, Harry T Orr4,5, Thomas F Westbrook1,6,8, Juan Botas1,2, Huda Y Zoghbi1,2,3,6.
Abstract
Many neurodegenerative disorders, such as Alzheimer's, Parkinson's and polyglutamine diseases, share a common pathogenic mechanism: the abnormal accumulation of disease-causing proteins, due to either the mutant protein's resistance to degradation or overexpression of the wild-type protein. We have developed a strategy to identify therapeutic entry points for such neurodegenerative disorders by screening for genetic networks that influence the levels of disease-driving proteins. We applied this approach, which integrates parallel cell-based and Drosophila genetic screens, to spinocerebellar ataxia type 1 (SCA1), a disease caused by expansion of a polyglutamine tract in ataxin 1 (ATXN1). Our approach revealed that downregulation of several components of the RAS-MAPK-MSK1 pathway decreases ATXN1 levels and suppresses neurodegeneration in Drosophila and mice. Importantly, pharmacological inhibitors of components of this pathway also decrease ATXN1 levels, suggesting that these components represent new therapeutic targets in mitigating SCA1. Collectively, these data reveal new therapeutic entry points for SCA1 and provide a proof-of-principle for tackling other classes of intractable neurodegenerative diseases.Entities:
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Year: 2013 PMID： 23719381 PMCID： PMC4020154 DOI： 10.1038/nature12204
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962