Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

National Institute On Aging

Investigators

Linked publications & trials

Abstract

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. Importantly, inhibition of the kinase activity of LRRK2 is now entering clinical trials and so it is critical to understand what the biological consequences of inhibited activity is, which we have approached using both genetic and pharmacological tools. We have followed up on prior publications from the lab identifying a role for LRRK2 at the lysosome. Overall, our data suggest that LRRK2 helps to repair damage to lysosomal membranes by triggering RAB phosphorylation and membrane sorting events. In several contexts, this appears to then be important for a pro-inflammatory state, both in IPSC-derived human microglia and in vivo. We have also examined ways in which such activities can be enumerated in an endogenous context and how this can be changed by autosomal dominant mutations.