Non-classical exocytosis of &agr;-synuclein is sensitive to folding states and promoted under stress conditions

다국어 초록 (Multilingual Abstract)

<P><I>J. Neurochem.</I> (2010) <B>113</B>, 1263–1274.</P><P>Abstract</P><P>Parkinson’s disease is characterized by deposition of misfolded/aggregated &agr;-synuclein proteins in multiple regions of the brain. Neurons can release &agr;-synuclein; through this release, pathological forms of &agr;-synuclein are propagated between neurons, and also cause neuroinflammation. In this study, we demonstrate that release of &agr;-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 &agr;-synuclein into vesicles. Both vesicle translocation and secretion were blocked by attachment of a highly stable, globular protein to &agr;-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 &agr;-synuclein than in the cellular protein. Together, these results suggest that structurally abnormal, damaged &agr;-synuclein proteins translocate preferentially into vesicles and are released from neuronal cells via exocytosis.</P>