title: Large α-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking.
abstract: 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.
authors: School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 790-784, Korea.
authors: Bong-Kyu
authors: BK
authors: Choi
authors: Mal-Gi
authors: MG
authors: Choi
authors: Jae-Yeol
authors: JY
authors: Kim
authors: Yoosoo
authors: Y
authors: Yang
authors: Ying
authors: Y
authors: Lai
authors: Dae-Hyuk
authors: DH
authors: Kweon
authors: Nam Ki
authors: NK
authors: Lee
authors: Yeon-Kyun
authors: YK
authors: Shin
mesh_terms: D000818:Animals; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology; D050356:Lipid Metabolism / Q000187:drug effects; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009498:Neurotoxins / Q000737:chemistry / Q000633:toxicity; D016716:PC12 Cells; D011485:Protein Binding; D020836:Protein Structure, Quaternary; D011510:Proteolipids / Q000378:metabolism; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000633:toxicity; D050600:SNARE Proteins / Q000502:physiology*; D022142:Secretory Vesicles / Q000187:drug effects / Q000502:physiology; D014161:Transduction, Genetic; D050988:Vesicle-Associated Membrane Protein 2 / Q000502:physiology; D051844:alpha-Synuclein / Q000737:chemistry* / Q000235:genetics / Q000502:physiology* / Q000633:toxicity
chemical_list: D009498:Neurotoxins; D011510:Proteolipids; D011993:Recombinant Fusion Proteins; D050600:SNARE Proteins; C494706:Vamp2 protein, rat; D050988:Vesicle-Associated Membrane Protein 2; D051844:alpha-Synuclein; C020485:proteoliposomes