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

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...

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Bibliographic Details
Published in:eLife 2020-04, Vol.9
Main Authors: 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
Format: Article
Language:English
Subjects:
Aging
Aging - metabolism
Alzheimer's disease
Animals
Artificial chromosomes
Brain
Brain - metabolism
Cell Biology
Cell culture
Cloning
Diseases
Drosophila
Drosophila Proteins - metabolism
Embryogenesis
Embryonic development
endolysosomal trafficking
Endosomes - metabolism
Gerontology
Guanosine triphosphatases
Homeostasis
Insects
Localization
Locomotion
Lysosomes - metabolism
Nervous system
Neurodegenerative diseases
Neurophysiology
Neuropil
Neuroscience
Phenotypes
Proteins
Rab7
Retina
Statistical analysis
Synaptic transmission
Synaptic Transmission - physiology
TBC1D5
Vesicular Transport Proteins - metabolism
VPS29
VPS35
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Summary: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 and are essential for development. In , we find that is dispensable for embryogenesis but required for retromer function in aging adults, including for synaptic transmission, survival, and locomotion. Unexpectedly, in mutants, Vps35 and Vps26 proteins are normally expressed and associated, but retromer is mislocalized from neuropil to soma with the Rab7 GTPase. Further, 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.
ISSN:2050-084X
2050-084X
DOI:10.7554/elife.51977