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

Author

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  • Jeehye Park

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine)

  • Ismael Al-Ramahi

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Qiumin Tan

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine)

  • Nissa Mollema

    (Institute for Translational Neuroscience, University of Minnesota
    University of Minnesota)

  • Javier R. Diaz-Garcia

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Tatiana Gallego-Flores

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Hsiang-Chih Lu

    (Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Program in Developmental Biology, Baylor College of Medicine)

  • Sarita Lagalwar

    (Institute for Translational Neuroscience, University of Minnesota
    University of Minnesota)

  • Lisa Duvick

    (Institute for Translational Neuroscience, University of Minnesota
    University of Minnesota)

  • Hyojin Kang

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Present addresses: Supercomputing Center, Korea Institute of Science and Technology Information, Daejeon 305-806, South Korea (H.K.); Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea (Y.L.).)

  • Yoontae Lee

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine
    Present addresses: Supercomputing Center, Korea Institute of Science and Technology Information, Daejeon 305-806, South Korea (H.K.); Department of Life Science, Pohang University of Science and Technology, Pohang, Kyungbuk 790-784, South Korea (Y.L.).)

  • Paymaan Jafar-Nejad

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Layal S. Sayegh

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Ronald Richman

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine)

  • Xiuyun Liu

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine)

  • Yan Gao

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Chad A. Shaw

    (Baylor College of Medicine)

  • J. Simon C. Arthur

    (MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK)

  • Harry T. Orr

    (Institute for Translational Neuroscience, University of Minnesota
    University of Minnesota)

  • Thomas F. Westbrook

    (Baylor College of Medicine
    Program in Developmental Biology, Baylor College of Medicine
    Baylor College of Medicine)

  • Juan Botas

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital)

  • Huda Y. Zoghbi

    (Baylor College of Medicine
    Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
    Howard Hughes Medical Institute, Baylor College of Medicine
    Program in Developmental Biology, Baylor College of Medicine)

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.

Suggested Citation

  • Jeehye Park & Ismael Al-Ramahi & Qiumin Tan & Nissa Mollema & Javier R. Diaz-Garcia & Tatiana Gallego-Flores & Hsiang-Chih Lu & Sarita Lagalwar & Lisa Duvick & Hyojin Kang & Yoontae Lee & Paymaan Jafa, 2013. "RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1," Nature, Nature, vol. 498(7454), pages 325-331, June.
  • Handle: RePEc:nat:nature:v:498:y:2013:i:7454:d:10.1038_nature12204
    DOI: 10.1038/nature12204
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    Cited by:

    1. Thomas Bourquard & Kwanghyuk Lee & Ismael Al-Ramahi & Minh Pham & Dillon Shapiro & Yashwanth Lagisetty & Shirin Soleimani & Samantha Mota & Kevin Wilhelm & Maryam Samieinasab & Young Won Kim & Eunna H, 2023. "Functional variants identify sex-specific genes and pathways in Alzheimer’s Disease," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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