{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:33:44Z","timestamp":1792791224985,"version":"4.5.0"},"reference-count":99,"publisher":"American Society for Cell Biology (ASCB)","issue":"1","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["MBoC"],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:p>\u03b1-Synuclein is a presynaptic protein that regulates synaptic vesicle (SV) trafficking. In Parkinson\u2019s disease (PD) and dementia with Lewy bodies (DLB), \u03b1-synuclein aberrantly accumulates throughout neurons, including at synapses. During neuronal activity, \u03b1-synuclein is reversibly phosphorylated at serine 129 (pS129). While pS129 comprises \u223c4% of total \u03b1-synuclein under physiological conditions, it dramatically increases in PD and DLB brains. The impacts of excess pS129 on synaptic function are currently unknown. We show here that compared with wild-type (WT) \u03b1-synuclein, pS129 exhibits increased binding and oligomerization on synaptic membranes and enhanced vesicle \u201cmicroclustering\u201d in vitro. Moreover, when acutely injected into lamprey reticulospinal axons, excess pS129 \u03b1-synuclein robustly localized to synapses and disrupted SV trafficking in an activity-dependent manner, as assessed by ultrastructural analysis. Specifically, pS129 caused a declustering and dispersion of SVs away from the synaptic vicinity, leading to a significant loss of total synaptic membrane. Live imaging further revealed altered SV cycling, as well as microclusters of recently endocytosed SVs moving away from synapses. Thus, excess pS129 caused an activity-dependent inhibition of SV trafficking via altered vesicle clustering\/reclustering. This work suggests that accumulation of pS129 at synapses in diseases like PD and DLB could have profound effects on SV dynamics.<\/jats:p>","DOI":"10.1091\/mbc.e23-07-0269","type":"journal-article","created":{"date-parts":[[2023,11,22]],"date-time":"2023-11-22T12:25:28Z","timestamp":1700655928000},"source":"Crossref","is-referenced-by-count":29,"title":["Excess phosphoserine-129 \u03b1-synuclein induces synaptic vesicle trafficking and declustering defects at a vertebrate synapse"],"prefix":"10.1091","volume":"35","author":[{"given":"Jaqulin N.","family":"Wallace","sequence":"first","affiliation":[{"name":"Eugene Bell Center for Regenerative Biology and Tissue Engineering, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary C.","family":"Crockford","sequence":"additional","affiliation":[{"name":"Eugene Bell Center for Regenerative Biology and Tissue Engineering, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"Rom\u00e1n-Vendrell","sequence":"additional","affiliation":[{"name":"Eugene Bell Center for Regenerative Biology and Tissue Engineering, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily B.","family":"Brady","sequence":"additional","affiliation":[{"name":"Eugene Bell Center for Regenerative Biology and Tissue Engineering, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Hoffmann","sequence":"additional","affiliation":[{"name":"Whitman Center, Marine Biological Laboratory, Woods Hole, MA 02543"},{"name":"Laboratory of Molecular Neuroscience, German Center for Neurodegenerative Diseases (DZNE), 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karina J.","family":"Vargas","sequence":"additional","affiliation":[{"name":"Eugene Bell Center for Regenerative Biology and Tissue Engineering, and"},{"name":"Department of Cell Biology, University of Pittsburgh, PA 15261"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mariana","family":"Potcoava","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL 60612"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M. 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