UC San Diego

Parkinson’s Disease (PD) is a neurodegenerative movement disorder that affects a high percentage of the elderly population over 60. Autosomal dominant point mutations in the Leucine-Rich Repeat Kinase (LRRK2) gene mark the most common cause of familial PD. The main features of LRRK2 that drive PD include but are not limited to its kinase activity and binding partners. However, cellular functions and interactors of PD-driving and wild-type LRRK2 are only partially defined. Therefore, characterizing LRRK2 binding partners becomes one of the top priorities in learning about the disease. Chapter 1 provides a detailed background on LRRK2, its known functions, and interactors. Chapter 2 demonstrates Rab38 as a novel kinase regulator of LRRK2 under healthy and pathologic physiological conditions with LRRK2 PD mutants in murine melanocytes. Moreover, Rab38 also mediates membrane association and cellular localization of LRRK2. Rab38 and its more widely studied homolog Rab32 have been treated as proteins of the same functions; my experiments elucidate more distinct functions of Rab38 and Rab32 in murine melanocytes. Chapter 3 delineates a well-known LRRK2 differential binding partner, 14-3-3, while using it to calibrate an affinity purification mass-spectrometry (AP-MS) system for novel LRRK2 interactor screening. CLIMP63 is believed to be a novel binding partner of LRRK2 in our first LFQ (label-free quantification) MS screen. While investigating the binding between CLIMP63 and LRRK2 WT and R1441G, I found that exogenous Myc-CLIMP63’s binding to LRRK2 is mediated by LRRK2 residues independent from S910/935, which calls for further investigation into its precise binding sites.