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

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 Jafar-Nejad, Layal S. Sayegh, Ronald Richman, Xiuyun Liu, Yan Gao, Chad A. Shaw, J. Simon C. Arthur, Harry T. Orr (), Thomas F. Westbrook (), Juan Botas () and Huda Y. Zoghbi ()
Additional contact information
Jeehye Park: Baylor College of Medicine
Ismael Al-Ramahi: Baylor College of Medicine
Qiumin Tan: Baylor College of Medicine
Nissa Mollema: Institute for Translational Neuroscience, University of Minnesota
Javier R. Diaz-Garcia: Baylor College of Medicine
Tatiana Gallego-Flores: Baylor College of Medicine
Hsiang-Chih Lu: Jan and Dan Duncan Neurological Research Institute at Texas Children’s Hospital
Sarita Lagalwar: Institute for Translational Neuroscience, University of Minnesota
Lisa Duvick: Institute for Translational Neuroscience, University of Minnesota
Hyojin Kang: Baylor College of Medicine
Yoontae Lee: Baylor College of Medicine
Paymaan Jafar-Nejad: Baylor College of Medicine
Layal S. Sayegh: Baylor College of Medicine
Ronald Richman: Baylor College of Medicine
Xiuyun Liu: Baylor College of Medicine
Yan Gao: Baylor College of Medicine
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
Thomas F. Westbrook: Baylor College of Medicine
Juan Botas: Baylor College of Medicine
Huda Y. Zoghbi: Baylor College of Medicine

Nature, 2013, vol. 498, issue 7454, 325-331

Abstract: 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.

Date: 2013
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DOI: 10.1038/nature12204

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