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

DOI Web Site 被引用文献32件
  • Andrew B. West
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Darren J. Moore
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Saskia Biskup
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Artem Bugayenko
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Wanli W. Smith
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Christopher A. Ross
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Valina L. Dawson
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205
  • Ted M. Dawson
    Institute for Cell Engineering, Departments of Neurology, Neuroscience, and Physiology, and Department of Psychiatry and Division of Neurobiology, 733 North Broadway, The Johns Hopkins University School of Medicine, Baltimore, MD 21205

書誌事項

公開日
2005-11-03
DOI
  • 10.1073/pnas.0507360102
公開者
Proceedings of the National Academy of Sciences

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説明

<jats:p> Mutations in the leucine-rich repeat kinase 2 gene ( <jats:italic>LRRK2</jats:italic> ) cause late-onset Parkinson's disease (PD) with a clinical appearance indistinguishable from idiopathic PD. Initial studies suggest that <jats:italic>LRRK2</jats:italic> mutations are the most common yet identified determinant of PD susceptibility, transmitted in an autosomal-dominant mode of inheritance. Herein, we characterize the <jats:italic>LRRK2</jats:italic> 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 R1441C do not have an obvious effect on protein steady-state levels, turnover, or localization. However, <jats:italic>in vitro</jats:italic> 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 <jats:italic>LRRK2</jats:italic> -linked disease with a central role for kinase activity in the development of PD. </jats:p>

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