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

Published

Journal Article

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 approximately 280 kDa and is present largely in the cytoplasm but also associates with the mitochondrial outer membrane. Familial-linked mutations G2019S or R1441C 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.

Full Text

Duke Authors

Cited Authors

  • West, AB; Moore, DJ; Biskup, S; Bugayenko, A; Smith, WW; Ross, CA; Dawson, VL; Dawson, TM

Published Date

  • November 15, 2005

Published In

Volume / Issue

  • 102 / 46

Start / End Page

  • 16842 - 16847

PubMed ID

  • 16269541

Pubmed Central ID

  • 16269541

International Standard Serial Number (ISSN)

  • 0027-8424

Digital Object Identifier (DOI)

  • 10.1073/pnas.0507360102

Language

  • eng

Conference Location

  • United States