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

Andrew B. West, Darren J. Moore, Catherine Choi, Shaida A. Andrabi, Xiaojie Li, Dustin Dikeman, Saskia Biskup, Zhenshui Zhang, Kah Leong Lim, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)223-232
Number of pages10
JournalHuman molecular genetics
Volume16
Issue number2
DOIs
StatePublished - Jan 15 2007

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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