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

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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.

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Figure 1: Integrative genetic screen identifies regulators of ATXN1(82Q) stability.
Figure 2: Modifiers shared between cell-based and in vivo screens.
Figure 3: Upstream MAPK pathway components regulate ATXN1 toxicity and levels.
Figure 4: MSK1 phosphorylates ATXN1 at S776 and controls its stability.
Figure 5: Pharmacological inhibition of the MAPK pathway decreases ATXN1 level.
Figure 6: Msk reduction rescues behavioural and pathological phenotypes in SCA1 mice.

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Acknowledgements

We thank the members of the Zoghbi, Botas, Orr and Westbrook laboratories for suggestions and discussions, and V. Brandt for editorial input. We also appreciate the help from CCSC and C-BASS cores at The Baylor College of Medicine (BCM) for FACS analysis and the confocal microscopy and mouse behavioural cores of the BCM Intellectual and Developmental Disabilities Research Center (HD024064). Thanks to J. Barrish at Texas Children’s Hospital for help with scanning electron microscopy. This work was supported by a Howard Hughes Medical Institute Collaborative Innovation Awards grant and grant NIH-NS42179 (J.B.) I.A.-R. was supported by an NIH Brain Disorders and Development training grant.

Author information

J.P., I.A.-R., Q.T., N.M., H.T.O., T.F.W., J.B. and H.Y.Z. designed the experiments. J.P., I.A.-R., Q.T., N.M., J.R.D.-G., T.G.-F., H.-C.L., S.L., L.D., H.K., Y.L., P.J.-N., L.S.S., R.R., X.L. and Y.G. performed the research. J.P., I.A.-R., Q.T., N.M., J.R.D.-G., T.G.-F., H.-C.L., S.L., L.D., H.K., Y.L., P.J.-N., C.A.S., J.S.C.A., H.T.O., T.F.W., J.B. and H.Y.Z. analysed and interpreted the data. J.P., I.A.-R., H.T.O., T.F.W., J.B. and H.Y.Z. wrote and edited the paper.

Correspondence to Harry T. Orr or Thomas F. Westbrook or Juan Botas or Huda Y. Zoghbi.

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Supplementary Information

This file contains the N number for Figure 6c in the main paper, Supplementary Figures 1-8, Supplementary Tables 1-4, the genotypes for Drosophila and additional references. (PDF 2136 kb)

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Park, J., Al-Ramahi, I., Tan, Q. et al. RAS–MAPK–MSK1 pathway modulates ataxin 1 protein levels and toxicity in SCA1. Nature 498, 325–331 (2013) doi:10.1038/nature12204

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