Clearance and secretion of α-synuclein by RTN3L-mediated endoplasmic reticulum autophagy

The misfolding and aggregation of α-synuclein (α-syn), an abundant synaptic protein, leads to the pathogenesis of Parkinson's disease and related synucleinopathies. The cell-to-cell propagation of seeding-competent α-syn is initiated by unconventional protein secretion, yet the physiological pathway(s) underlying this process remain poorly defined. Here we show that α-syn secretion in human cells is mediated by Reticulon-3L (RTN3L)-dependent 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 α-syn into an acidic endolysosomal compartment. Increasing concentrations of α-syn disrupt ER-lysosome traffic, and α-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 α-syn secretion. These findings suggest that pathogenic α-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.