title: 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 Rab8a, similarly impairs retromer trafficking, secretory autophagy and Golgi-derived vesicle secretion, thus demonstrating converging roles of two PD genes TMEM230 and LRRK2 on Rab8a function, and suggesting that retromer and secretory dysfunction play an important role in PD pathogenesis.
authors.forename: Myung Jong
authors.initials: MJ
authors.lastname: Kim
authors.forename: Han-Xiang
authors.initials: HX
authors.lastname: Deng
authors.forename: Yvette C
authors.initials: YC
authors.lastname: Wong
authors.forename: Teepu
authors.initials: T
authors.lastname: Siddique
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D006056:Golgi Apparatus / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D010300:Parkinson Disease / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D022142:Secretory Vesicles / Q000235:genetics / Q000378:metabolism*; D013949:Thymus Extracts; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D013949:Thymus Extracts; C031407:thymostimulin; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; C082377:RAB8A protein, human; D020691:rab GTP-Binding Proteins