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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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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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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