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 been able to fully model the most likely clinical use of LRRK2 kinase inhibition, which is to chronically treat a model with endogenous PD-associated mutation in vivo. These studies showed that we can return markers of enhanced LRRK2 activity to baseline with a degree of precision over a chronic time period, suggesting likely efficacy at a biochemical level in humans. One consequence of deficiency or inhibition of LRRK2 is to modify the lysosomal proteome, especially in sensitive tissue such as kidney. This led us to ask why LRRK2, which is typically broadly distributed in the cell, would affect lysosomes specifically. We discovered a new mechanism by which LRRK2 affects lysosomal response to damage. After recruitment to damaged lysosomal membranes, LRRK2 phosphorylates Rab proteins that then recruit the motor adaptor protein JIP4, which controls tubulation of the lysosomal membrane. Ongoing work is to extend these observations into additional molecular events.