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

Eszter Zavodszky, Matthew N.J. Seaman (), Kevin Moreau, Maria Jimenez-Sanchez, Sophia Y. Breusegem, Michael E. Harbour and David C. Rubinsztein ()
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Eszter Zavodszky: Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK
Matthew N.J. Seaman: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Cambridge CB2 0XY, UK
Kevin Moreau: Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK
Maria Jimenez-Sanchez: Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK
Sophia Y. Breusegem: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Cambridge CB2 0XY, UK
Michael E. Harbour: Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Cambridge CB2 0XY, UK
David C. Rubinsztein: Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK

Nature Communications, 2014, vol. 5, issue 1, 1-16

Abstract: Abstract 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.

Date: 2014
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DOI: 10.1038/ncomms4828

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