LRRK2 gene mutations are a common cause of Parkinsons disease. The protein product of the gene has both kinase and GTPase activities. Because there are mutations in both kinase and GTPase domains, we consider that both activities are probably important for pathogenesis of Parkinsons disease. As such, we are trying to understand each activity in turn and how they interact. In the past year we have mainly focussed on the role that LRRK2 plays in vesicular trafficking. Using a combination of cell (iPS) and rodent (knockout and knockin) models, we have clearly delineated that loss of LRRK2 results in abnormalities in the autophagy-lysosome system. We have identified a series of candidate proteins that link LRRK2 to lysosomal function in vivo and are validating the mechanism of action by comparing a series of mutant alleles. In parallel, and to provide a more mechanistic platform, we are comparing the same alleles in cell lines.
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