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PMID: 24819384 Published · epublish English Journal Article Research Support, Non-U.S. Gov't

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

Nature communications ·Vol. 5 ·2014-05-13 ·Pages 3828

Zavodszky E, Seaman MN, Moreau K, Jimenez-Sanchez M, Breusegem SY, Harbour ME, Rubinsztein DC

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.

MeSH Terms
Autophagy/genetics Autophagy-Related Proteins Cell Line, Tumor Endosomes/metabolism Golgi Apparatus/metabolism HeLa Cells Humans Membrane Proteins/metabolism Parkinson Disease/genetics Protein Transport/genetics Vesicular Transport Proteins/genetics,metabolism Wiskott-Aldrich Syndrome Protein Family/metabolism
Chemicals
Atg9a protein, human Autophagy-Related Proteins Membrane Proteins VPS35 protein, human Vesicular Transport Proteins WASF1 protein, human Wiskott-Aldrich Syndrome Protein Family
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Zavodszky Eszter
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].
Seaman Matthew N J
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].
Moreau Kevin
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.
Jimenez-Sanchez Maria
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.
Breusegem Sophia Y
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
Harbour Michael E
Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
Rubinsztein David C
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.
Supplementary Concepts
Parkinson Disease, Familial, Type 1 (Disease)
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Article Info
Journal
Nature communications
Abbr.
Nat Commun
ISSN
2041-1723
DOI
10.1038/ncomms4828
Published
2014-05-13
Epub
2014-00-13
Pages
3828
Language
English
Region
England
NLM ID
101528555
PMCID
PMC4024763
Subset
IM
Grants
Medical Research Council · G0701444 · United Kingdom
Wellcome Trust · 089703 · United Kingdom
Medical Research Council · MR/L007533/1 · United Kingdom
Medical Research Council · G0700750 · United Kingdom
Medical Research Council · MC_G1000734 · United Kingdom
Wellcome Trust · 095317 · United Kingdom
Wellcome Trust · 100140 · United Kingdom
Corrections
CommentIn
PMID: 24963965
External Links
PubMed source DOI: 10.1038/ncomms4828 PMC Full Text View journal details
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