title: Mutation in VPS35 associated with Parkinson's disease impairs WASH complex association and inhibits autophagy.
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.
authors.affiliation: 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].
authors.forename: Eszter
authors.initials: E
authors.lastname: Zavodszky
authors.affiliation: 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].
authors.forename: Matthew N J
authors.initials: MN
authors.lastname: Seaman
authors.affiliation: 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.
authors.forename: Kevin
authors.initials: K
authors.lastname: Moreau
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: Jimenez-Sanchez
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Sophia Y
authors.initials: SY
authors.lastname: Breusegem
authors.affiliation: Department of Clinical Biochemistry, Cambridge Institute for Medical Research, University of Cambridge, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Cambridge CB2 0XY, UK.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Harbour
authors.affiliation: 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.
authors.forename: David C
authors.initials: DC
authors.lastname: Rubinsztein
mesh_terms: D001343:Autophagy / Q000235:genetics*; D000071183:Autophagy-Related Proteins; D045744:Cell Line, Tumor; D011992:Endosomes / Q000378:metabolism*; D006056:Golgi Apparatus / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D010300:Parkinson Disease / Q000235:genetics*; D021381:Protein Transport / Q000235:genetics; D033921:Vesicular Transport Proteins / Q000235:genetics* / Q000378:metabolism; D051300:Wiskott-Aldrich Syndrome Protein Family / Q000378:metabolism
chemical_list: C574794:ATG9A protein, human; D000071183:Autophagy-Related Proteins; D008565:Membrane Proteins; C419573:VPS35 protein, human; D033921:Vesicular Transport Proteins; C114864:WASF1 protein, human; D051300:Wiskott-Aldrich Syndrome Protein Family