Nature Neuroscience
- 9, 1231 - 1233 (2006)
Published online: 17 September 2006; | doi:10.1038/nn1776
Kinase activity of mutant LRRK2 mediates neuronal toxicityWanli W Smith1, Zhong Pei1, Haibing Jiang1, Valina L Dawson2, 3, 4, 5, Ted M Dawson2, 4, 5 & Christopher A Ross1, 2, 51
Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 2
Departments of Neuroscience and Neurology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 3
Department of Physiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 4
Institute For Cell Engineering, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA. 5
Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, Maryland 21287, USA.
Correspondence should be addressed to Christopher A Ross caross@jhu.edu or Wanli W Smith wsmith60@jhmi.edu LRRK2LRRK2GTPGTPaseMutations in the the leucine-rich repeat kinase-2 (LRRK2) gene cause autosomal-dominant Parkinson disease and some cases of sporadic Parkinson disease. Here we found that LRRK2 kinase activity was regulated by GTP via the intrinsic GTPase Roc domain, and alterations of LRRK2 protein that reduced kinase activity of mutant LRRK2 correspondingly reduced neuronal toxicity. These data elucidate the pathogenesis of LRRK2-linked Parkinson disease, potentially illuminate mechanisms of sporadic Parkinson disease and suggest therapeutic targets.
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