Molecular biology of the cellJul 15, 2026

Removal and release of alpha-synuclein through RTN3L-controlled cell cleanup process

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 16, 2026

Abstract

The secretion of α-synuclein in human cells is mediated by Reticulon-3L-dependent endoplasmic reticulum autophagy.

α-synuclein misfolding and aggregation is linked to Parkinson's disease and related conditions.
Reticulon-3L plays a critical role in the secretion of α-synuclein by facilitating a protein quality-control pathway.
Collaboration with autophagy regulators, including FIP200, is essential for transporting α-synuclein to endolysosomal compartments.
Elevated levels of α-synuclein disrupt the normal traffic between the endoplasmic reticulum and lysosomes.
Secretion of α-synuclein may occur due to the fusion of vesicles with the cell surface, influenced by SNARE proteins.

Simplified

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, that mediate fusion at the cell surface, disrupt 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 mis-regulated, could contribute to the spread of neurodegenerative pathology.

Removal and release of alpha-synuclein through RTN3L-controlled cell cleanup process

Abstract

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