The Parkinson's disease-linked protein TMEM230 is required for Rab8a-mediated secretory vesicle trafficking and retromer trafficking.

ABSTRACT: TMEM230 is a newly identified Parkinson's disease (PD) gene encoding a transmembrane protein whose cellular and pathogenic roles remain largely unknown. Here, we demonstrate that loss of TMEM230 disrupts retromer cargo CI-M6PR (cation-independent mannose 6-phosphate receptor) trafficking and autophagic cargo degradation rates. TMEM230 depletion further inhibits extracellular secretion of the autophagic cargo p62 and immature lysosomal hydrolases in Golgi-derived vesicles leading to their intracellular accumulation, and is specifically mediated by loss of the small GTPase Rab8a. Importantly, PD-linked TMEM230 variants also induce retromer mislocalization, defective cargo trafficking, and impaired autophagy. Finally, we show that knockdown of another PD gene, LRRK2, which phosphorylates Rab8

SUBMITTER: Kim MJ 

PROVIDER: S-EPMC6251589 | biostudies-literature | 2017 Feb

REPOSITORIES: biostudies-literature