2. Academic Validation
  3. Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy

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

  • Nat Commun. 2014 May 13;5:3828. doi: 10.1038/ncomms4828.
Eszter Zavodszky 1,  Matthew N J Seaman 2,  Kevin Moreau 3,  Maria Jimenez-Sanchez 3,  Sophia Y Breusegem 4,  Michael E Harbour 4,  David C Rubinsztein 3
Affiliations

Affiliations

  • 1 1] Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK [2].
  • 2 1] Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK [2].
  • 3 Department of Medical Genetics, Cambridge Institute for Medical Research, Cambridge Biomedical Campus, University of Cambridge, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 0XY, UK.
  • 4 Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
PMID: 24819384 DOI: 10.1038/ncomms4828
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.

Figures