Lrrk2 phosphorylates alpha synuclein at serine 129: Parkinson disease implications.

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Biochem Biophys Res Commun 2009 Jul;

Authors: Hong Qing, Winnie Wong, Edith G McGeer, Patrick L McGeer

Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, BC, Canada V6T 1Z3; School of Life Science and Technology, Beijing Institute of Technology, 5 South Zhongguancun Street, Haidian District, Beijing 100081, PR China.

Mutations in the alpha synuclein gene (SNCA) are the most potent cause of autosomal dominant Parkinson disease (PD) while mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause. We hypothesized that a direct interaction may exist between their protein products. Here we show that full-length Lrrk2 or fragments containing its kinase domain have a significant capacity to phosphorylate recombinant alpha synuclein (Asyn) at serine 129. Such phosphorylated Asyn is the major component of pathological deposits in PD. We further show that the G2019S mutation in Lrrk2, which is the most common genetic determinant of PD, has a significantly greater capacity than wild-type Lrrk2 to phosphorylate Asyn. This suggests that the G2019S mutant protein may cause PD by generating pathological levels of phosphorylated Asyn. Controlling Lrrk2 Asyn phosphokinase activity may be an approach to disease modifying therapy for PD and other synucleinopathies.

PMID: 19576176 [PubMed - as supplied by publisher]

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