Non-classical exocytosis of alpha-synuclein is sensitive to folding states and promoted under stress conditions.

Department of Anatomy, School of Medicine, Konkuk University, Seoul, Korea.
Journal of Neurochemistry (Impact Factor: 4.24). 03/2010; 113(5):1263-74. DOI: 10.1111/j.1471-4159.2010.06695.x
Source: PubMed

ABSTRACT 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.

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