RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1

Jeehye Park, Ismael Al-Ramahi, Quimin Tan, Nissa Mollema, Javier R. Diaz-Garcia, Tatiana Gallego-Flores, Hsiang-Chih Lu, Sarita Lagalwar, Lisa Duvick, Hyojin Kang, Yoontae Lee, Paymaan Jafar-Nejad, Layal S. Sayegh, Ronald Richman, Xiuyun Liu, Yan Gao, Chad A. Shaw, J. Simon C. Arthur, Harry T. Orr, Thomas F. WestbrookJuan Botas, H.Y. Zoghbi

    Research output: Contribution to journalArticlepeer-review

    95 Citations (Scopus)

    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.
    Original languageEnglish
    Pages (from-to)325-331
    Number of pages7
    JournalNature
    Volume498
    Issue number7454
    DOIs
    Publication statusPublished - 2013

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