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.
Highlights
The endolysosomal membrane system comprises a dynamic network of interconnected compartments that mediates sorting or degradation of endocytosed proteins (Klumperman and Raposo, 2014; Repnik et al, 2013)
Vps291 homozygotes are recovered at ratios below Mendelian expectation (Figure 1—figure supplement 1A)
Our discovery that Vps29 is dispensable for Drosophila embryogenesis provides an unexpected opportunity to examine the neuronal consequences of retromer dysfunction in vivo
Summary
The endolysosomal membrane system comprises a dynamic network of interconnected compartments that mediates sorting or degradation of endocytosed proteins (Klumperman and Raposo, 2014; Repnik et al, 2013). Retromer is a complex that recycles selected protein cargoes from the endosome to the trans-Golgi network or the plasma membrane (Burd and Cullen, 2014; Lucas and Hierro, 2017). Despite its emerging importance in neurodegenerative disease, the requirements of retromer in neurons and within the aging nervous system remain incompletely understood. In the absence of retromer, many protein cargoes are misdirected to the lysosome (Burd and Cullen, 2014; Lucas and Hierro, 2017; Wang and Bellen, 2015), potentially overwhelming degradative capacity, leading to lysosomal expansion and cellular stress. We identify an unexpected requirement for Vps in the regulation of retromer localization, and further highlight a role in synaptic vesicle recycling and lysosomal function in the aging brain
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