{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,16]],"date-time":"2026-06-16T03:36:50Z","timestamp":1781581010996,"version":"3.54.5"},"reference-count":32,"publisher":"Rockefeller University Press","issue":"4","content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,11,24]]},"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.1083\/jcb.201406026","type":"journal-article","created":{"date-parts":[[2014,11,24]],"date-time":"2014-11-24T16:23:28Z","timestamp":1416846208000},"page":"453-462","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":94,"title":["Reduced synaptic vesicle protein degradation at lysosomes curbs <i>TBC1D24\/sky<\/i>-induced neurodegeneration"],"prefix":"10.1083","volume":"207","author":[{"given":"Ana Clara","family":"Fernandes","sequence":"first","affiliation":[{"name":"VIB Center for the Biology of Disease 1 and 2"},{"name":"Center for Human Genetics Laboratory of Neuronal Communication, KU Leuven, 3000 Leuven, Belgium 1 and 2"},{"name":"VIB Center for the Biology of Disease 1 and 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