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Cited by 533

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

West, Andrew B., Moore, Darren J., Choi, Catherine, Andrabi, Shaida A., Li, Xiaojie, Dikeman, Dustin, Biskup, Saskia, Zhang, Zhenshui, Lim, Kah-Leong, Dawson, Valina L., Dawson, Ted M.·2007·Human Molecular Genetics
DOI 10.1093/hmg/ddl471
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Abstract

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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Research works printed but not linked: 30

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Metadata

Authors
West, A. B., Moore, D. J., Choi, C., Andrabi, S. A., Li, X., Dikeman, D., Biskup, S., Zhang, Z., Lim, K.-L., Dawson, V. L., & Dawson, T. M.
Venue
Human Molecular Genetics
Publisher
Oxford University Press (OUP)
Published
2007-01-02
Volume
16
Issue
2
Pages
223-232
ISSN
  • 1460-2083
  • 0964-6906
DOI
10.1093/hmg/ddl471
Cited by
533
References
1
Language
en

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