Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy

• Published in: Nature communications Vol. 5; no. 1; p. 3828
• Main Authors: Zavodszky, Eszter, Seaman, Matthew N.J., Moreau, Kevin, Jimenez-Sanchez, Maria, Breusegem, Sophia Y., Harbour, Michael E., Rubinsztein, David C.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 13-05-2014; Nature Publishing Group; Nature Pub. Group
• Subjects: 13; 13/106; 13/109; 13/89; 14; 14/1; 14/19; 14/63; 631/208/737; 631/80/82/39; 692/420; 692/699/375/365/1718; 82; Autophagy - genetics; Autophagy-Related Proteins; Cell Line, Tumor; Endosomes - metabolism; Golgi Apparatus - metabolism; HeLa Cells; Humanities and Social Sciences; Humans; Membrane Proteins - metabolism; multidisciplinary; Parkinson Disease - genetics; Protein Transport - genetics; Science; Science (multidisciplinary); Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; Wiskott-Aldrich Syndrome Protein Family - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4828

Endosomal protein sorting controls the localization of many physiologically important proteins and is linked to several neurodegenerative diseases. VPS35 is a component of the retromer complex, which mediates endosome-to-Golgi retrieval of membrane proteins such as the cation-independent mannose 6-phosphate receptor. Furthermore, retromer is also required for the endosomal recruitment of the actin nucleation promoting WASH complex. The VPS35 D620N mutation causes a rare form of autosomal-dominant Parkinson’s disease (PD). Here we show that this mutant associates poorly with the WASH complex and impairs WASH recruitment to endosomes. Autophagy is impaired in cells expressing PD-mutant VPS35 or lacking WASH. The autophagy defects can be explained, at least in part, by abnormal trafficking of the autophagy protein ATG9A. Thus, the PD-causing D620N mutation in VPS35 restricts WASH complex recruitment to endosomes, and reveals a novel role for the WASH complex in autophagosome formation.
Parkinson’s disease can be caused by a rare mutation in the protein VPS35, but the mechanism responsible for this is largely unknown. Here, Zavodszky
et al.
show that this mutation leads to defects in the recruitment of endosomal protein sorting machinery and consequent inhibition of autophagy in cells.