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

Ye, Hui, Ojelade, Shamsideen A, Li-Kroeger, David, Zuo, Zhongyuan, Wang, Liping, Li, Yarong, Gu, Jessica YJ, Tepass, Ulrich, Rodal, Avital Adah, Bellen, Hugo J, Shulman, Joshua M·2020·eLife
DOI 10.7554/elife.51977PMC PMC7182434

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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.

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Metadata

Authors
Ye, H., Ojelade, S. A., Li-Kroeger, D., Zuo, Z., Wang, L., Li, Y., Gu, J. Y., Tepass, U., Rodal, A. A., Bellen, H. J., & Shulman, J. M.
Affiliations
  • Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, United States
  • Department of Neurology, Baylor College of Medicine, Houston, United States
  • Program in Developmental Biology, Baylor College of Medicine, Houston, United States
  • Department of Cell and Systems Biology, University of Toronto, Ontario, Canada
  • Department of Biology, Brandeis University, Waltham, United States
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2020-04-14
Volume
9
ISSN
2050-084X
DOI
10.7554/elife.51977
PMC
PMC7182434
Cited by
51
References
11
Language
en
Licence
Funders
  • National Institutes of Health (R01AG053960, U01AG046161, U01AG061357, U54AG065187, R01NS103967, U54HD083092, P30CA125123)
  • Burroughs Wellcome Fund (Career Award for Medical Scientists, Postdoctoral Enrichment Program Award (BWF-1017399))
  • Howard Hughes Medical Institute
  • Robert and Renee Belfer Family Foundation
  • Alzheimer's Association (AARFD-16-442630)

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