title: The synaptic vesicle SNARE neuronal Synaptobrevin promotes endolysosomal degradation and prevents neurodegeneration.
abstract: Soluble NSF attachment protein receptors (SNAREs) are the core proteins in membrane fusion. The neuron-specific synaptic v-SNARE n-syb (neuronal Synaptobrevin) plays a key role during synaptic vesicle exocytosis. In this paper, we report that loss of n-syb caused slow neurodegeneration independent of its role in neurotransmitter release in adult Drosophila melanogaster photoreceptor neurons. In addition to synaptic vesicles, n-Syb localized to endosomal vesicles. Loss of n-syb lead to endosomal accumulations, transmembrane protein degradation defects, and a secondary increase in autophagy. Our evidence suggests a primary defect of impaired delivery of vesicles that contain degradation proteins, including the acidification-activated Cathepsin proteases and the neuron-specific proton pump and V0 adenosine triphosphatase component V100. Overexpressing V100 partially rescued n-syb-dependent degeneration through an acidification-independent endosomal sorting mechanism. Collectively, these findings reveal a role for n-Syb in a neuron-specific sort-and-degrade mechanism that protects neurons from degeneration. Our findings further shed light on which intraneuronal compartments exhibit increased or decreased neurotoxicity.
authors.affiliation: Department of Physiology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Haberman
authors.forename: W Ryan
authors.initials: WR
authors.lastname: Williamson
authors.forename: Daniel
authors.initials: D
authors.lastname: Epstein
authors.forename: Dong
authors.initials: D
authors.lastname: Wang
authors.forename: Srisha
authors.initials: S
authors.lastname: Rina
authors.forename: Ian A
authors.initials: IA
authors.lastname: Meinertzhagen
authors.forename: P Robin
authors.initials: PR
authors.lastname: Hiesinger
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D011992:Endosomes / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D059748:Proteolysis; D050683:R-SNARE Proteins / Q000235:genetics / Q000378:metabolism*; D013572:Synaptic Vesicles / Q000378:metabolism*; D025262:Vacuolar Proton-Translocating ATPases / Q000235:genetics / Q000378:metabolism
chemical_list: D029721:Drosophila Proteins; D050683:R-SNARE Proteins; C084068:nsyb protein, Drosophila; D025262:Vacuolar Proton-Translocating ATPases; C550849:Vha100-1 protein, Drosophila