Abstract
L-DOPA–induced dyskinesia, the rate-limiting side effect in the therapy of Parkinson's disease, is mediated by activation of mammalian target of rapamycin (mTOR) signaling in the striatum. We found that Ras homolog enriched in striatum (Rhes), a striatal-specific protein, binds to and activates mTOR. Moreover, Rhes−/− mice showed reduced striatal mTOR signaling and diminished dyskinesia, but maintained motor improvement on L-DOPA treatment, suggesting a therapeutic benefit for Rhes-binding drugs.
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Acknowledgements
We thank R. Romano, D. Vitucci, V. Marsili, P. Scherer and S. Korde for valuable technical assistance, and R. DiLauro (University of Naples) for providing the Rhes−/− mice. This work was supported by United States Public Health Service grant MH18501 (S.H.S.) and a grant of the Cure for Huntington's Disease Initiative (S.H.S.).
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S.S. initiated the project and conducted the mTOR binding and activation experiments, which were further characterized by R.G.M. A.U. initiated the dyskinesia and mTOR experiments in mice. S.S. and S.H.S. further conceived and designed the experiments. F.N. and F.E. conducted the L-DOPA and behavioral experiments, under the direction of A.U. R.B. generated the Rhes constructs. S.K. performed the in vitro mTOR activity assay. R.T. and N.S. contributed to the mTOR activity and binding experiments. S.H.S. wrote the manuscript with input from R.G.M., S.S. and A.U.
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Subramaniam, S., Napolitano, F., Mealer, R. et al. Rhes, a striatal-enriched small G protein, mediates mTOR signaling and L-DOPA–induced dyskinesia. Nat Neurosci 15, 191–193 (2012). https://doi.org/10.1038/nn.2994
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DOI: https://doi.org/10.1038/nn.2994
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