Title: Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration
Authors: Dos Santos Oliveira Fernandes, Ana Clara *
Uytterhoeven, Valerie *
Kuenen, Sabine #
Wang, Yu-Chun
Slabbaert, Jan #
Swerts, Jef
Kasprowicz, Jaroslaw #
Aerts, Stein
Verstreken, Patrik # ×
Issue Date: 24-Nov-2014
Publisher: Rockefeller Institute Press
Series Title: Journal of Cell Biology vol:207 issue:4 pages:453-462
Abstract: Synaptic demise and accumulation of dysfunctional
proteins are thought of as common features in neurodegeneration.
However, the mechanisms by which
synaptic proteins turn over remain elusive. In this paper,
we study Drosophila melanogaster lacking active
TBC1D24/Skywalker (Sky), a protein that in humans
causes severe neurodegeneration, epilepsy, and DOOR
(deafness, onychdystrophy, osteodystrophy, and mental
retardation) syndrome, and identify endosome-to-lysosome
trafficking as a mechanism for degradation of synaptic
vesicle-associated proteins. In fly sky mutants, synaptic
vesicles traveled excessively to endosomes. Using chimeric
fluorescent timers, we show that synaptic vesicle-associated
proteins were younger on average, suggesting that older
proteins are more efficiently degraded. Using a genetic
screen, we find that reducing endosomal-to-lysosomal
trafficking, controlled by the homotypic fusion and vacuole
protein sorting (HOPS) complex, rescued the neurotransmission
and neurodegeneration defects in sky mutants. Consistently,
synaptic vesicle proteins were older in HOPS
complex mutants, and these mutants also showed reduced
neurotransmission. Our findings define a mechanism
in which synaptic transmission is facilitated by efficient
protein turnover at lysosomes and identify a potential strategy
to suppress defects arising from TBC1D24 mutations
in humans.
ISSN: 0021-9525
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory of Neuronal Communication
* (joint) first author
× corresponding author
# (joint) last author

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