Alexandra Unapanta, Farbod Shavarebi, Jacob Porath, Yiyi Shen, Carson Balen, Albert Nguyen, Josh Tseng, Weng Si Leong, Michelle Liu, Pawel Lis, Santiago M Di Pietro, Annie Hiniker
Point mutations in leucine-rich repeat kinase 2 (LRRK2) cause Parkinson's Disease (PD) and augment LRRK2's kinase activity. However, cellular pathways that endogenously enhance LRRK2 kinase function have not been identified. While overexpressed Rab29 draws LRRK2 to Golgi membranes to increase LRRK2 kinase activity, there is little evidence that endogenous Rab29 performs this function under physiological conditions. Here we identify Rab38 as a novel physiologic regulator of LRRK2 in melanocytes. In mouse melanocytes, which express high levels of Rab38, Rab32, and Rab29, knockdown (or CRISPR knockout) of Rab38, but not Rab32 or Rab29, decreases phosphorylation of multiple LRRK2 substrates, including Rab10 and Rab12, by both endogenous LRRK2 and exogenous PD-mutant LRRK2...
August 23, 2023: Journal of Biological Chemistry