Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease

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Abstract

Leucine-rich repeat kinase-2 (LRRK2) mutations are a common cause of Parkinson's disease. Here we identify inhibitors of LRRK2 kinase that are protective in in vitro and in vivo models of LRRK2-induced neurodegeneration. These results establish that LRRK2-induced degeneration of neurons in vivo is kinase dependent and that LRRK2 kinase inhibition provides a potential new neuroprotective paradigm for the treatment of Parkinson's disease.

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Figure 1: Identification of inhibitors of LRRK2 kinase.
Figure 2: LRRK2 kinase inhibition protects against LRRK2-induced neuronal toxicity.

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Acknowledgements

We thank C. Burris and L. Lotta for packaging helper virus–free amplicons. C. Cook, K. Kehoe, J. Dunmore and C. Eckman provided technical support for some of the in vivo HSV studies. We also thank G. and K. Caldwell and S. Hamamichi for helpful discussions. This work was supported by grants from the US National Institutes of Health, P50NS38377, R01ES014470 (K.A.M.-Z.), R01-AG023593 (W.J.B.), R00-NS058111 (A.B.W.), NS36420 (H.J.F.) and Army Medical Research and Materiel Command, DAMD17-02-1-0695 (H.J.F.), the Mayo Foundation and the Michael J. Fox Foundation.

Author information

B.D.L., J.V., L.P., A.B.W., V.L.D. and T.M.D. designed the experiments. B.D.L., J.V., H.S.K., Y.I.L. and J.-H.S. generated data. K.A.M.-Z., W.J.B. and H.J.F. generated HSV-encoded LRRK2s. B.D.L. and J.V. analyzed data. B.D.L., V.L.D. and T.M.D. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Correspondence to Valina L Dawson or Ted M Dawson.

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Competing interests

T.M.D. is a paid consultant to Merck KGAA. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies.

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Supplementary Figures 1–6, Supplementary Tables 1–3 and Supplementary Methods (PDF 1295 kb)

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