Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking
| Autor: | Dae-Hyuk Kweon, Mal-Gi Choi, Yeon-Kyun Shin, Nam Ki Lee, Jae-Yeol Kim, Ying Lai, Bong-Kyu Choi, Yoosoo Yang |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Vesicle-Associated Membrane Protein 2
Proteolipids Recombinant Fusion Proteins animal diseases Vesicle docking Models Neurological Neurotoxins Biology PC12 Cells Exocytosis chemistry.chemical_compound Transduction Genetic Dopamine medicine Animals heterocyclic compounds Protein Structure Quaternary Neurons Multidisciplinary Dementia with Lewy bodies Secretory Vesicles Vesicle Neurotoxicity Biological Sciences Lipid Metabolism medicine.disease Rats nervous system diseases Cell biology Monomer nervous system chemistry alpha-Synuclein SNARE Proteins SNARE complex Function (biology) Protein Binding medicine.drug |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:4087-4092 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1218424110 |
| Popis: | Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of α-synuclein (α-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of α-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large α-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large α-Syn oligomers preferentially bind to the N-terminal domain of a vesicular SNARE protein, synaptobrevin-2, which blocks SNARE-mediated lipid mixing by preventing SNARE complex formation. In sharp contrast, the α-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large α-Syn oligomers. Thus, the results suggest that large α-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity. |
| Databáze: | OpenAIRE |
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