UC San Diego

Parkinson’s Disease (PD) is the second most common neurodegenerative disorder, currently affecting over 7 million individuals worldwide. Clinically, PD results in progressive cell death of dopaminergic neurons in the basal ganglia and substantia nigra, but what drives this cell death is still unclear. Point mutations to the Leucine-Rich Repeat Kinase 2 (LRRK2) gene are the most common cause of inherited PD and importantly, LRRK2-PD phenocopies sporadic PD. Thus, better understanding the roles of the LRRK2 protein could provide insights into the driving forces behind PD pathogenesis and progression. LRRK2 has several protein interaction domains and has been shown to be regulated by a number of interactors, yet adequate characterization of the LRRK2 protein interactome is still lacking. Chapter 1 will provide a comprehensive background on LRRK2 biology detailing its structure, function and interactions to inform topics explored in subsequent chapters. Chapter 2 identifies the E3 ubiquitin ligase TRIM1 as a novel regulator of LRRK2 microtubule localization and LRRK2 degradation by the proteasome. Chapter 3 comprises the first report of endogenous regulation of LRRK2 by a Rab protein. Endogenous Rab38 regulates LRRK2 subcellular localization in B16-F10 mouse melanocytes. Finally, Chapter 4 explores the effects of chloroquine and IFN-γ treatment on LRRK2 localization and activity in macrophages. This chapter reveals a novel interaction between LRRK2 and Rab32 in RAW 264.7 macrophages under IFN-γ treatment. These results highlight the need for further research into LRRK2 protein interactors which could regulate LRRK2 activity through a number of mechanisms in a cell-type specific manner.