1. Cell Biology
  2. Neuroscience

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
https://doi.org/10.7554/eLife.51977
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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

Version 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.

Metrics

  • 3,540
    Page views
  • 519
    Downloads
  • 31
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  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

Share this article

https://doi.org/10.7554/eLife.51977

Categories and tags

Research organism

Further reading

    1. Cell Biology
    2. Chromosomes and Gene Expression

    Heat stress impairs centromere structure and segregation of meiotic chromosomes in Arabidopsis

    Lucie Crhak Khaitova, Pavlina Mikulkova ... Karel Riha
    Research Article

    Heat stress is a major threat to global crop production, and understanding its impact on plant fertility is crucial for developing climate-resilient crops. Despite the known negative effects of heat stress on plant reproduction, the underlying molecular mechanisms remain poorly understood. Here, we investigated the impact of elevated temperature on centromere structure and chromosome segregation during meiosis in Arabidopsis thaliana. Consistent with previous studies, heat stress leads to a decline in fertility and micronuclei formation in pollen mother cells. Our results reveal that elevated temperature causes a decrease in the amount of centromeric histone and the kinetochore protein BMF1 at meiotic centromeres with increasing temperature. Furthermore, we show that heat stress increases the duration of meiotic divisions and prolongs the activity of the spindle assembly checkpoint during meiosis I, indicating an impaired efficiency of the kinetochore attachments to spindle microtubules. Our analysis of mutants with reduced levels of centromeric histone suggests that weakened centromeres sensitize plants to elevated temperature, resulting in meiotic defects and reduced fertility even at moderate temperatures. These results indicate that the structure and functionality of meiotic centromeres in Arabidopsis are highly sensitive to heat stress, and suggest that centromeres and kinetochores may represent a critical bottleneck in plant adaptation to increasing temperatures.

    1. Cell Biology

    High-altitude hypoxia exposure inhibits erythrophagocytosis by inducing macrophage ferroptosis in the spleen

    Wan-ping Yang, Mei-qi Li ... Qian-qian Luo
    Research Article

    High-altitude polycythemia (HAPC) affects individuals living at high altitudes, characterized by increased red blood cells (RBCs) production in response to hypoxic conditions. The exact mechanisms behind HAPC are not fully understood. We utilized a mouse model exposed to hypobaric hypoxia (HH), replicating the environmental conditions experienced at 6000 m above sea level, coupled with in vitro analysis of primary splenic macrophages under 1% O2 to investigate these mechanisms. Our findings indicate that HH significantly boosts erythropoiesis, leading to erythrocytosis and splenic changes, including initial contraction to splenomegaly over 14 days. A notable decrease in red pulp macrophages (RPMs) in the spleen, essential for RBCs processing, was observed, correlating with increased iron release and signs of ferroptosis. Prolonged exposure to hypoxia further exacerbated these effects, mirrored in human peripheral blood mononuclear cells. Single-cell sequencing showed a marked reduction in macrophage populations, affecting the spleen’s ability to clear RBCs and contributing to splenomegaly. Our findings suggest splenic ferroptosis contributes to decreased RPMs, affecting erythrophagocytosis and potentially fostering continuous RBCs production in HAPC. These insights could guide the development of targeted therapies for HAPC, emphasizing the importance of splenic macrophages in disease pathology.

    1. Cell Biology

    Golgi Apparatus: Making progress

    Jurgen Denecke
    Insight

    Mapping proteins in and associated with the Golgi apparatus reveals how this cellular compartment emerges in budding yeast and progresses over time.