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Biochem Biophys Res Commun. 2009 Dec 25;390(4):1229-34. doi: 10.1016/j.bbrc.2009.10.126. Epub 2009 Oct 28.

Lrrk2 interaction with alpha-synuclein in diffuse Lewy body disease.

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Kinsmen Laboratory of Neurological Research, University of British Columbia, Vancouver, British Columbia, Canada V6T 1Z3.


Mutations of the leucine-rich repeat kinase 2 (LRRK2) gene are the leading cause of genetically inherited Parkinson's disease (PD) and its more severe variant diffuse Lewy body disease (DLB). Pathological mutations in Lrrk2 are autosomal dominant, suggesting a gain of function. Mutations in alpha-synuclein also produce autosomal dominant disease. Here we report an interaction between Lrrk2 and alpha-synuclein in a series of diffuse Lewy body (DLB) cases and in an oxidative stress cell based assay. All five cases of DLB, but none of five controls, showed co-immunoprecipitation of Lrrk2 and alpha-synuclein in soluble brain extracts. Colocalization was also found in pathological deposits in DLB postmortem brains by double immunostaining. In HEK cells transfected simultaneously with plasmids expressing Lrrk2 and alpha-synuclein, co-immunoprecipitation of Lrrk2 and alpha-synuclein was detected when they were exposed to oxidative stress by H(2)O(2). Taken together, these results suggest the possibility that in PD and related synucleinopathies, oxidative stress upregulates alpha-syn and Lrrk2 expression, paving the way for pathological interactions. New therapeutic approaches to PD and the synucleinopathies may result from limiting the interaction between Lrrk2 and alpha-synuclein.

[Indexed for MEDLINE]

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