Kinase activity of mutant LRRK2 mediates neuronal toxicity

Wanli W. Smith; Zhong Pei; Haibing Jiang; Valina L. Dawson; Ted M. Dawson; Christopher A. Ross

doi:10.1038/nn1776

Kinase activity of mutant LRRK2 mediates neuronal toxicity

Wanli W. Smith, Zhong Pei, Haibing Jiang, Valina L. Dawson, Ted M. Dawson, Christopher A. Ross

School of Medicine

Research output: Contribution to journal › Article › peer-review

500 Scopus citations

Abstract

Mutations 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.

Original language	English (US)
Pages (from-to)	1231-1233
Number of pages	3
Journal	Nature neuroscience
Volume	9
Issue number	10
DOIs	https://doi.org/10.1038/nn1776
State	Published - Oct 2006

ASJC Scopus subject areas

Neuroscience(all)

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title = "Kinase activity of mutant LRRK2 mediates neuronal toxicity",

abstract = "Mutations 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.",

author = "Smith, {Wanli W.} and Zhong Pei and Haibing Jiang and Dawson, {Valina L.} and Dawson, {Ted M.} and Ross, {Christopher A.}",

note = "Funding Information: This work was supported by the US National Institutes of Health, the National Institute of Neurological Disorders and Stroke (R21NS055684-01 and NS38377) and the National Parkinson{\textquoteright}s Disease Foundation.",

year = "2006",

month = oct,

doi = "10.1038/nn1776",

language = "English (US)",

volume = "9",

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T1 - Kinase activity of mutant LRRK2 mediates neuronal toxicity

AU - Smith, Wanli W.

AU - Pei, Zhong

AU - Jiang, Haibing

AU - Dawson, Valina L.

AU - Dawson, Ted M.

AU - Ross, Christopher A.

N1 - Funding Information: This work was supported by the US National Institutes of Health, the National Institute of Neurological Disorders and Stroke (R21NS055684-01 and NS38377) and the National Parkinson’s Disease Foundation.

PY - 2006/10

Y1 - 2006/10

N2 - Mutations 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.

AB - Mutations 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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Kinase activity of mutant LRRK2 mediates neuronal toxicity

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