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Here we show that \u03b1-syn secretion in human cells is mediated by Reticulon-3L (RTN3L)\u2013dependent endoplasmic reticulum autophagy (ER-phagy), a conserved protein quality-control pathway that safeguards ER protein homeostasis. We also demonstrate that RTN3L cooperates with several autophagy regulators, including the ULK1 cofactor FIP200, to drive the delivery of \u03b1-syn into an acidic endolysosomal compartment. Increasing concentrations of \u03b1-syn disrupt ER-lysosome traffic, and \u03b1-syn-containing vesicles appear to be rerouted to the cell surface. Consistent with this proposal, knockdown of vesicle-associated SNAREs, which mediate fusion at the cell surface, disrupts \u03b1-syn secretion. These findings suggest that pathogenic \u03b1-syn secretion arises as a by-product of a physiological clearance mechanism, driven by the fusion of autophagosome-derived vesicles with the plasma membrane. Our results provide a conceptual framework for understanding how an intracellular proteostasis pathway, when misregulated, could contribute to the spread of neurodegenerative pathology.<\/jats:p>","DOI":"10.1091\/mbc.e26-03-0138","type":"journal-article","created":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T15:45:04Z","timestamp":1784130304000},"source":"Crossref","is-referenced-by-count":0,"title":["Clearance and secretion of \u03b1-synuclein by RTN3L-mediated endoplasmic reticulum autophagy"],"prefix":"10.1091","volume":"37","author":[{"given":"Yihong","family":"Ye","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Biology, National Institute of Diabetes, Digestive, and Kidney Disease, National Institutes of Health, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Cellular and Molecular Medicine, University of California at San Diego, La 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