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 have been particularly looking for shared effects of multiple mutations that are found in many different functional domains of the molecule. We have now developed methods to measure the endogenous autophosphorylation of LRRK2 in vivo. We have shown that, as expected, mutation in LRRK2 result in enhanced autophosphorylation suggesting a gain of function mechanism. Importantly, we have also been able to block the enhanced activity using specific LRRK2 kinase inhibitors, indicating potential use of this class of compounds in treating LRRK2-related disease. We are currently following up these observations with additional time and concentration-dependency of application of these compounds to understand the long-term consequences of inhibition of kinase activity in vivo.