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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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References

  1. Gasser, T. Expert Rev. Mol. Med. 11, e22 (2009).

    Article  Google Scholar 

  2. Greggio, E. et al. Neurobiol. Dis. 23, 329–341 (2006).

    Article  CAS  Google Scholar 

  3. Smith, W.W. et al. Nat. Neurosci. 9, 1231–1233 (2006).

    Article  CAS  Google Scholar 

  4. West, A.B. et al. Hum. Mol. Genet. 16, 223–232 (2007).

    Article  CAS  Google Scholar 

  5. Whaley, N.R., Uitti, R.J., Dickson, D.W., Farrer, M.J. & Wszolek, Z.K. J. Neural Transm. Suppl. 70, 221–229 (2006).

    Article  CAS  Google Scholar 

  6. Mata, I.F., Wedemeyer, W.J., Farrer, M.J., Taylor, J.P. & Gallo, K.A. Trends Neurosci. 29, 286–293 (2006).

    Article  CAS  Google Scholar 

  7. Chin, P.C. et al. J. Neurochem. 90, 595–608 (2004).

    Article  CAS  Google Scholar 

  8. Imai, Y. et al. EMBO J. 27, 2432–2443 (2008).

    Article  CAS  Google Scholar 

  9. Smith, W.W. et al. Proc. Natl. Acad. Sci. USA 102, 18676–18681 (2005).

    Article  CAS  Google Scholar 

  10. Leclerc, S. et al. J. Biol. Chem. 276, 251–260 (2001).

    Article  CAS  Google Scholar 

  11. Wang, W. et al. Neuropharmacology 52, 1678–1684 (2007).

    Article  CAS  Google Scholar 

  12. Anand, V.S. et al. FEBS J. 276, 466–478 (2009).

    Article  CAS  Google Scholar 

  13. Covy, J.P. & Giasson, B.I. Biochem. Biophys. Res. Commun. 378, 473–477 (2009).

    Article  CAS  Google Scholar 

  14. Nichols, R.J. et al. Biochem. J. 424, 47–60 (2009).

    Article  CAS  Google Scholar 

  15. Reichling, L.J. & Riddle, S.M. Biochem. Biophys. Res. Commun. 384, 255–258 (2009).

    Article  CAS  Google Scholar 

Download references

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.

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Author notes

  1. Andrew B West

    Present address: Present address: Center for Neurodegeneration and Experimental Therapeutics, University of Alabama School of Medicine, Birmingham, Alabama, USA.,

  2. Valina L Dawson and Ted M Dawson: These authors contributed equally to this work.

Authors and Affiliations

  1. Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Byoung Dae Lee, Joo-Ho Shin, Andrew B West, Han Seok Ko, Yun-Il Lee, Valina L Dawson & Ted M Dawson

  2. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Byoung Dae Lee, Joo-Ho Shin, Andrew B West, Han Seok Ko, Yun-Il Lee, Valina L Dawson & Ted M Dawson

  3. Department of Neuroscience, Mayo Clinic College of Medicine, Jacksonville, Florida, USA

    Jackalina VanKampen & Leonard Petrucelli

  4. Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA

    Kathleen A Maguire-Zeiss

  5. Department of Neurology, Center for Neural Development and Disease, University of Rochester Medical Center, Rochester, New York, USA

    William J Bowers

  6. Office of the Executive Vice President and Executive Dean, Georgetown University Medical Center, Washington, DC, USA

    Howard J Federoff

  7. Department of Neurology, Georgetown University Medical Center, Washington, DC, USA

    Howard J Federoff

  8. Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Valina L Dawson & Ted M Dawson

  9. Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA

    Valina L Dawson

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  1. Byoung Dae Lee
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Contributions

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.

Corresponding authors

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.

Supplementary information

Supplementary Text and Figures

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

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Lee, B., Shin, JH., VanKampen, J. et al. Inhibitors of leucine-rich repeat kinase-2 protect against models of Parkinson's disease. Nat Med 16, 998–1000 (2010). https://doi.org/10.1038/nm.2199

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  • DOI: https://doi.org/10.1038/nm.2199

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