Retromer Subunit, VPS29, Regulates Synaptic Transmission and is Required for Endolysosomal Function in the Aging Brain

Overview

Journal Elife

Specialty Biology

Date 2020 Apr 15

PMID 32286230

Citations 27

Authors

Hui Ye

Shamsideen A Ojelade

David Li-Kroeger

Zhongyuan Zuo

Liping Wang

Yarong Li

Jessica Yj Gu

Ulrich Tepass

Avital Adah Rodal

Hugo J Bellen

Joshua M Shulman

Affiliations

Soon will be listed here.

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 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.

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