Parkinson's disease-associated mutations in leucine-rich repeat kinase 2 augment kinase activity

Andrew B. West, Darren J. Moore, Saskia Biskup, Artem Bugayenko, Wanli W. Smith, Christopher A. Ross, Valina L. Dawson, Ted M. Dawson

Research output: Contribution to journalArticlepeer-review

Abstract

Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that LRRK2 mutations are the most common yet identified determinant of PD susceptibility, transmitted in an autosomal-dominant mode of inheritance. Herein, we characterize the LRRK2 gene and transcript in human brain and subclone the predominant ORF. Exogenously expressed LRRK2 protein migrates at ≈280 kDa and is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Familial-linked mutations G2019S or R144K do not have an obvious effect on protein steady-state levels, turnover, or localization. However, in vitro kinase assays using full-length recombinant LRRK2 reveal an increase in activity caused by familial-linked mutations in both autophosphorylation and the phosphorylation of a generic substrate. These results suggest a gain-of-function mechanism for LRRK2-linked disease with a central role for kinase activity in the development of PD.

Original languageEnglish (US)
Pages (from-to)16842-16847
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume102
Issue number46
DOIs
StatePublished - Nov 15 2005

Keywords

  • Dardarin
  • PARK8
  • Parkinsonism

ASJC Scopus subject areas

  • General

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