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 found that Lrrk2 deficiency results in co-ordinated changes in the expression of proteins associated with lysosomes, but also cytoskeletal and protein translation pathways. Using mouse knockouts, we can now tell how these differences between genotypes relate to the aging process. Our recent results show that lysosomal disturbances occur earlier than other changes, suggesting that these might be the primary events in response to loss of Lrrk2. We are currently testing whether such differences are causal for phenotypes by crossing Lrrk2 knockouts with animals lacking key lysosomal enzymes.
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