Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain

  1. Hui Ye
  2. Shamsideen A Ojelade
  3. David Li-Kroeger
  4. Zhongyuan Zuo
  5. Liping Wang
  6. Yarong Li
  7. Jessica Y J Gu
  8. Ulrich Tepass
  9. Avital Adah Rodal
  10. Hugo J Bellen
  11. Joshua M Shulman  Is a corresponding author
  1. Baylor College of Medicine, United States
  2. UT Southwestern Medical Center, United States
  3. University of Toronto, Canada
  4. Brandeis University, United States

Abstract

Retromer, including Vps35, Vps26, and Vps29, is a protein complex responsible for recycling proteins within the endolysosomal pathway. Although implicated in both Parkinson's and Alzheimer's disease, our understanding of retromer function in the adult brain remains limited, in part because Vps35 and Vps26 are essential for development. In Drosophila, we find that Vps29 is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in Vps29 mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, Vps29 phenotypes are suppressed by reducing Rab7 or overexpressing the GTPase activating protein, TBC1D5. With aging, retromer insufficiency triggers progressive endolysosomal dysfunction, with ultrastructural evidence of impaired substrate clearance and lysosomal stress. Our results reveal the role of Vps29 in retromer localization and function, highlighting requirements for brain homeostasis in aging.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Hui Ye

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  2. Shamsideen A Ojelade

    Psychiatry, UT Southwestern Medical Center, Dallas, United States
    Competing interests
    No competing interests declared.
  3. David Li-Kroeger

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6473-7691
  4. Zhongyuan Zuo

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  5. Liping Wang

    Program in Developmental Biology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  6. Yarong Li

    Department of Neurology, Baylor College of Medicine, Houston, United States
    Competing interests
    No competing interests declared.
  7. Jessica Y J Gu

    Department of Cell and Systems Biology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  8. Ulrich Tepass

    Department of Cell and Systems Biology, University of Toronto, Toronto, Canada
    Competing interests
    No competing interests declared.
  9. Avital Adah Rodal

    Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2051-8304
  10. Hugo J Bellen

    Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
    Competing interests
    Hugo J Bellen, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5992-5989
  11. Joshua M Shulman

    Department of Neurology, Baylor College of Medicine, Houston, United States
    For correspondence
    joshua.shulman@bcm.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1835-1971

Funding

National Institutes of Health (R01AG053960,R01NS103967,U01AG046161,U01AG061357,P30CA125123,U54HD083092)

  • Avital Adah Rodal
  • Joshua M Shulman

Burroughs Wellcome Fund (Career Award for Medical Scientists,Postdoctoral Enrichment Program Award (BWF-1017399))

  • Shamsideen A Ojelade
  • Joshua M Shulman

Alzheimer's Association (AARFD-16-442630)

  • Shamsideen A Ojelade

Howard Hughes Medical Institute

  • Hugo J Bellen

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. K VijayRaghavan, National Centre for Biological Sciences, Tata Institute of Fundamental Research, India

Publication history

  1. Received: September 18, 2019
  2. Accepted: April 11, 2020
  3. Accepted Manuscript published: April 14, 2020 (version 1)
  4. Version of Record published: April 24, 2020 (version 2)

Copyright

© 2020, Ye et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Hui Ye
  2. Shamsideen A Ojelade
  3. David Li-Kroeger
  4. Zhongyuan Zuo
  5. Liping Wang
  6. Yarong Li
  7. Jessica Y J Gu
  8. Ulrich Tepass
  9. Avital Adah Rodal
  10. Hugo J Bellen
  11. Joshua M Shulman
(2020)
Retromer subunit, VPS29, regulates synaptic transmission and is required for endolysosomal function in the aging brain
eLife 9:e51977.
https://doi.org/10.7554/eLife.51977

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