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, PDlinked 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.
Original language | English (US) |
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Pages (from-to) | 729-741 |
Number of pages | 13 |
Journal | Human molecular genetics |
Volume | 26 |
Issue number | 4 |
DOIs | |
State | Published - Feb 15 2017 |
Funding
We thank Dr Fumio Kishi (Kawasaki Medical School, Japan) for the FLAG-VPS35 construct. We thank Hyunkyung Jeong for helpful comments on this manuscript. NIH grant (R01NS076054 to D.K., R01NS099623 to H.D., R21 NS074366 to H.D., NS050641 to T.S.); Les Turner ALS Foundation Professorship (T.S.).
ASJC Scopus subject areas
- Genetics(clinical)
- Genetics
- Molecular Biology