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Kinase activity of mutant LRRK2 mediates neuronal toxicity

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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.

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Figure 1: Alteration of the key residues of LRRK2 reduces its kinase activity in an autophosphorylation assay.
Figure 2: Alteration of mutant LRRK2 activity reduces its neuronal toxicity.
Figure 3: Binding of GTP to LRRK2 requires the GTPase-like Roc domain and leads to stimulation of LRRK2 kinase activity.

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Acknowledgements

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.

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Authors and Affiliations

  1. Department of Psychiatry, Division of Neurobiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Wanli W Smith, Zhong Pei, Haibing Jiang & Christopher A Ross

  2. Departments of Neuroscience and Neurology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Valina L Dawson, Ted M Dawson & Christopher A Ross

  3. Department of Physiology, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Valina L Dawson

  4. Institute For Cell Engineering, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Valina L Dawson & Ted M Dawson

  5. Program in Cellular and Molecular Medicine, Johns Hopkins University School of Medicine, CMSC 8-121, 600 North Wolfe Street, Baltimore, 21287, Maryland, USA

    Valina L Dawson, Ted M Dawson & Christopher A Ross

Authors
  1. Wanli W Smith
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  2. Zhong Pei
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  3. Haibing Jiang
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  4. Valina L Dawson
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  5. Ted M Dawson
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  6. Christopher A Ross
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Correspondence to Wanli W Smith or Christopher A Ross.

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The authors declare no competing financial interests.

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Smith, W., Pei, Z., Jiang, H. et al. Kinase activity of mutant LRRK2 mediates neuronal toxicity. Nat Neurosci 9, 1231–1233 (2006). https://doi.org/10.1038/nn1776

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  • DOI: https://doi.org/10.1038/nn1776

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