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Nature. 2013 Jun 20;498(7454):325-331. doi: 10.1038/nature12204. Epub 2013 May 29.

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

Author information

1
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
2
Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital, Houston, Texas 77030, USA.
3
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas 77030, USA.
4
Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, USA.
5
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota 55455, USA.
6
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
7
MRC Protein Phosphorylation Unit, School of Life Sciences, University of Dundee, Dundee, DD1 5EH, UK.
8
Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
#
Contributed equally

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.

PMID:
23719381
PMCID:
PMC4020154
DOI:
10.1038/nature12204
[Indexed for MEDLINE]
Free PMC Article

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