Reduced synaptic vesicle protein degradation at lysosomes curbs TBC1D24/sky-induced neurodegeneration
0301 basic medicine
0303 health sciences
Membrane Glycoproteins
Hearing Loss, Sensorineural
GTPase-Activating Proteins
Neuromuscular Junction
Membrane Proteins
Nails, Malformed
Nerve Tissue Proteins
Neurodegenerative Diseases
Endosomes
Craniofacial Abnormalities
DNA-Binding Proteins
03 medical and health sciences
Drosophila melanogaster
Intellectual Disability
Mutation
Animals
Drosophila Proteins
Humans
Carrier Proteins
Lysosomes
10. No inequality
Hand Deformities, Congenital
Research Articles
DOI:
10.1083/jcb.201406026
Publication Date:
2014-11-24T16:23:28Z
AUTHORS (9)
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.
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