Leucine rich repeat kinase 2 and dominantly inherited Parkinson disease

National Institute On Aging

Investigators

Linked publications, trials & patents

Abstract

Our main aim in this project is to understand how mutations across many different domains of LRRK2 cause dominantly inherited Parkinsons disease. We previously reported that there was a diminishment of kinase function by a risk factor variant in LRRK2, G2385R. We know now that, mechanistically, the mutant version of LRRK2 is unstable likely due to misfolding at the C-terminus that promotes binding of chaperones. As this event is separated physically from the kinase domain, our working hypothesis is that the C-terminus and kinase domains interact with each other. We are currently extending this work to examine whether loss of function is also seen in the mouse version of the protein, which would allow us to test the idea of loss of function in vivo using knockin mice.