TY - JOUR
T1 - RAS-MAPK-MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1
AU - Park, Jeehye
AU - Al-Ramahi, Ismael
AU - Tan, Qiumin
AU - Mollema, Nissa
AU - Diaz-Garcia, Javier R.
AU - Gallego-Flores, Tatiana
AU - Lu, Hsiang Chih
AU - Lagalwar, Sarita
AU - Duvick, Lisa
AU - Kang, Hyojin
AU - Lee, Yoontae
AU - Jafar-Nejad, Paymaan
AU - Sayegh, Layal S.
AU - Richman, Ronald
AU - Liu, Xiuyun
AU - Gao, Yan
AU - Shaw, Chad A.
AU - Arthur, J. Simon C
AU - Orr, Harry T.
AU - Westbrook, Thomas F.
AU - Botas, Juan
AU - Zoghbi, Huda Y.
PY - 2013
Y1 - 2013
N2 - 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.
AB - 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.
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U2 - 10.1038/nature12204
DO - 10.1038/nature12204
M3 - Article
C2 - 23719381
AN - SCOPUS:84879414055
SN - 0028-0836
VL - 498
SP - 325
EP - 331
JO - Nature
JF - Nature
IS - 7454
ER -
