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Human Molecular Genetics Advance Access originally published online on January 2, 2007
Human Molecular Genetics 2007 16(2):223-232; doi:10.1093/hmg/ddl471
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Parkinson's disease-associated mutations in LRRK2 link enhanced GTP-binding and kinase activities to neuronal toxicity

Andrew B. West1,2, Darren J. Moore1,2, Catherine Choi1,2, Shaida A. Andrabi1,2, Xiaojie Li1,2, Dustin Dikeman1,2, Saskia Biskup1,2, Zhenshui Zhang5, Kah-Leong Lim5, Valina L. Dawson1,2,3,4 and Ted M. Dawson1,2,3,*

1 Institute for Cell Engineering, 2 Department of Neurology, 3 Department of Neuroscience, 4 Department of Physiology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA and 5 National Neuroscience Institute, Singapore, Singapore

* To whom correspondence should be addressed at: 733 N. Broadway, Suite 731, Broadway Research Building, Baltimore, MD 21205, USA. Tel: +1 4106143359; Fax: +1 4106149568; Email: tdawson{at}jhmi.edu

Received November 13, 2006; Accepted December 14, 2006

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease indistinguishable from idiopathic disease. The mechanisms whereby missense alterations in the LRRK2 gene initiate neurodegeneration remain unknown. Here, we demonstrate that seven of 10 suspected familial-linked mutations result in increased kinase activity. Functional and disease-associated mutations in conserved residues reveal the critical link between intrinsic guanosine triphosphatase (GTPase) activity and downstream kinase activity. LRRK2 kinase activity requires GTPase activity, whereas GTPase activity functions independently of kinase activity. Both LRRK2 kinase and GTPase activity are required for neurotoxicity and potentiate peroxide-induced cell death, although LRRK2 does not function as a canonical MAP–kinase–kinase–kinase. These results suggest a link between LRRK2 kinase activity and pathogenic mechanisms relating to neurodegeneration, further supporting a gain-of-function role for LRRK2 mutations.


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