title: Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting.
abstract: Recycling synaptic vesicles (SVs) transit through early endosomal sorting stations, which raises a fundamental question: are SVs sorted toward endolysosomal pathways? Here, we used snapin mutants as tools to assess how endolysosomal sorting and trafficking impact presynaptic activity in wild-type and snapin(-/-) neurons. Snapin acts as a dynein adaptor that mediates the retrograde transport of late endosomes (LEs) and interacts with dysbindin, a subunit of the endosomal sorting complex BLOC-1. Expressing dynein-binding defective snapin mutants induced SV accumulation at presynaptic terminals, mimicking the snapin(-/-) phenotype. Conversely, over-expressing snapin reduced SV pool size by enhancing SV trafficking to the endolysosomal pathway. Using a SV-targeted Ca(2+) sensor, we demonstrate that snapin-dysbindin interaction regulates SV positional priming through BLOC-1/AP-3-dependent sorting. Our study reveals a bipartite regulation of presynaptic activity by endolysosomal trafficking and sorting: LE transport regulates SV pool size, and BLOC-1/AP-3-dependent sorting fine-tunes the Ca(2+) sensitivity of SV release. Therefore, our study provides new mechanistic insights into the maintenance and regulation of SV pool size and synchronized SV fusion through snapin-mediated LE trafficking and endosomal sorting.
authors.affiliation: Synaptic Functions Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA.
authors.forename: Jerome
authors.initials: J
authors.lastname: Di Giovanni
authors.affiliation: Synaptic Functions Section, The Porter Neuroscience Research Center, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA shengz@ninds.nih.gov.
authors.forename: Zu-Hang
authors.initials: ZH
authors.lastname: Sheng
mesh_terms: D000818:Animals; D001692:Biological Transport / Q000502:physiology; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002458:Cell Fractionation; D002478:Cells, Cultured; D002942:Circular Dichroism; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; D007150:Immunohistochemistry; D008247:Lysosomes / Q000378:metabolism*; D051379:Mice; D008854:Microscopy, Electron; D008959:Models, Neurological; D009474:Neurons / Q000502:physiology*; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism*; D059008:Time-Lapse Imaging; D033921:Vesicular Transport Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: C498992:Dtnbp1 protein, mouse; D000074765:Dysbindin; D049029:Dystrophin-Associated Proteins; C498451:Snapin protein, mouse; D033921:Vesicular Transport Proteins; D002118:Calcium
keywords: BLOC‐1; dynein motor; dysbindin; endosomal sorting and transport; snapin