Journal
JOURNAL OF NEUROCHEMISTRY
Volume 113, Issue 5, Pages 1263-1274Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1471-4159.2010.06695.x
Keywords
misfolding; neurodegenerative disease; Parkinson's disease; protein aggregation; secretion
Categories
Funding
- Ministry of Education, Science and Technology, Republic of Korea [20090084180]
- Korea government [20090083737]
- Korean Government (MOEHRD) [KRF-2006-311-C00135]
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P>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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