Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. In the current period, we have confirmed previous data that mutant LRRK2 can be toxic to cells in culture when expressed acutely. In collaboration with Steve Finkbeiner at UCSF, we found that mutant LRRK2 is toxic to cells in a manner that depends on a-synuclein. This toxic effect is shared between multiple mutations and is minimized when an inactive (kinase dead) version of LRRK2 is substituted for active versions, although some of the effects are related to protein level rather than activity per se. These results support the argument that although different mutations affect different parts of the LRRK2 molecule and therefore have divergent molecular effects, they all share some convergent property(s) that lead to detrimental effects. We have recently shown that LRRK2 interacts with a series of other proteins, including two that have been nominated as candidate genes for genetic risk in Parkinson's disease, Rab7L1 and GAK. Following up on the function of the complex of proteins, we found that LRRK2 cooperates with Rab7L1 and GAK to promote the removal of a subset of vesicles derived from the trans-golgi network by a process that involves the autophagy-lysosome system. Importantly, all mutations in LRRK2 that we have assayed to date promote this effect, suggesting it is a common property of pathogenic variants. We are currently following this work up in systems that should allow us to assay mutations at the endogenous level.
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