IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v5y2014i1d10.1038_ncomms4828.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • Eszter Zavodszky & Matthew N.J. Seaman & Kevin Moreau & Maria Jimenez-Sanchez & Sophia Y. Breusegem & Michael E. Harbour & David C. Rubinsztein, 2014. "Mutation in VPS35 associated with Parkinson’s disease impairs WASH complex association and inhibits autophagy," Nature Communications, Nature, vol. 5(1), pages 1-16, September.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4828
    DOI: 10.1038/ncomms4828
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms4828
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms4828?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. James L. Daly & Chris M. Danson & Philip A. Lewis & Lu Zhao & Sara Riccardo & Lucio Filippo & Davide Cacchiarelli & Daehoon Lee & Stephen J. Cross & Kate J. Heesom & Wen-Cheng Xiong & Andrea Ballabio , 2023. "Multi-omic approach characterises the neuroprotective role of retromer in regulating lysosomal health," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    2. Cheng Fu & Nan Yang & Jen-Zen Chuang & Nobuyuki Nakajima & Satoshi Iraha & Neeta Roy & Zhenquan Wu & Zhichun Jiang & Wataru Otsu & Roxana A. Radu & Howard Hua Yang & Maxwell Ping Lee & Tilla S. Worgal, 2024. "Mutant mice with rod-specific VPS35 deletion exhibit retinal α-synuclein pathology-associated degeneration," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms4828. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.