UCSF

Mutations in the gene encoding leucine-rich repeat kinase 2 (LRRK2) are the most common known cause for Parkinson’s disease (PD) and are associated with several other diseases, including cancer and autoimmune disease. Excitingly, several strategies to modulate LRRK2 activity in the brain are currently being tested in clinical trials for PD. Yet, there remain many unanswered questions as to how LRRK2 mutations affect cellular homeostasis and ultimately cause disease. Increasing our understanding of the cellular biology surrounding LRRK2 function is certain to aid in the acceleration of drug discovery and development in PD. In Chapter 1, I broadly summarize the role of LRRK2 in PD and reported LRRK2 molecular and cellular functions. In particular, I describe the unanswered question of how PD-causing mutations in the kinase and GTPase domains of LRRK2 differentially affect observed LRRK2 kinase activity in cells. In Chapter 2, I present my published work detailing distinct cellular effects of PD-causing mutations in either the GTPase or kinase domain of LRRK2. Specifically, I found that GTPase-inactivating mutations strongly increase LRRK2 localization to endosomes upon inhibition of endosomal maturation. Under the same conditions, kinase-activating mutations only modestly affect LRRK2 localization and wild-type LRRK2 localization is minimally affected. I further demonstrate that the extent of LRRK2 endosomal localization is directly related to observed levels of LRRK2 substrate phosphorylation. Through this work, I provide a rationale for why PD-causing mutations across LRRK2 domains lead to differing levels of substrate phosphorylation in cells. Overall, my work highlights the importance of LRRK2’s GTPase domain for the protein’s cellular localization and activity and suggests that therapeutic strategies targeting LRRK2 GTPase function or localization may be beneficial for PD.