GTPase function of Leucine rich repeat kinase 2

National Institute On Aging

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Abstract

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 Parkinson's disease. As such, we are trying to understand each activity in turn and how they interact. We have been focusing on how LRRK2 interacts physically with components of the endolysosomal system, including the GARP complex as well as clathrin and clathrin adaptor proteins. Collectively, these data have shown that LRRK2 mutations have subtle but consistent effects on protein trafficking in a variety of cell types. To further support this work, we have also reported a series of IPSC lines with a variety of natural and hypothesis testing mutations that can be used to interrogate these effects. We predict that a key event mediating the effects of LRRK2 mutations is likely to be via microglial reactivity, via the NFAT pathway. We have also examined the role of endogenous LRRK2 deficiency, as chemical inhibitors are currently in phase 3 clinical trials for Parkinson's disease. However, in mice at least it is possible to lack LRRK2 and a key endolysosomal partner, RAB29, and not have neurological abnormalities as evaluated by behavior or neuronal survival. This result suggests that these pathways should be able to be safely targeted in humans.