Non‐classical exocytosis of α‐synuclein is sensitive to folding states and promoted under stress conditions

Parkinson's disease is characterized by deposition of misfolded/aggregated alpha-synuclein proteins in multiple regions of the brain. Neurons can release alpha-synuclein; through this release, pathological forms of alpha-synuclein are propagated between neurons, and also cause neuroinflammation. In this study, we demonstrate that release of alpha-synuclein is consistently increased under various protein misfolding stress conditions in both neuroblastoma and primary neuron models. This release is mediated by a non-classical, endoplasmic reticulum (ER)/Golgi-independent exocytosis, and stress-induced release coincides with increased translocation of alpha-synuclein into vesicles. Both vesicle translocation and secretion were blocked by attachment of a highly stable, globular protein to alpha-synuclein, whereas forced protein misfolding resulted in an increase in both of these activities. Mass spectrometry analysis showed a higher degree of oxidative modification in secreted alpha-synuclein than in the cellular protein. Together, these results suggest that structurally abnormal, damaged alpha-synuclein proteins translocate preferentially into vesicles and are released from neuronal cells via exocytosis.