Choi, Bong-Kyu Choi, Mal-Gi Kim, Jae-Yeol Yang, Yoosoo Lai, Ying Kweon, Dae-Hyuk Lee, Nam Ki Shin, Yeon-Kyun 2024-01-20T12:34:35Z 2024-01-20T12:34:35Z 2021-09-01 2013-03-05 0027-8424 https://pubs.kist.re.kr/handle/201004/128252 Parkinson disease and dementia with Lewy bodies are featured with the formation of Lewy bodies composed mostly of alpha-synuclein (alpha-Syn) in the brain. Although evidence indicates that the large oligomeric or protofibril forms of alpha-Syn are neurotoxic agents, the detailed mechanisms of the toxic functions of the oligomers remain unclear. Here, we show that large alpha-Syn oligomers efficiently inhibit neuronal SNARE-mediated vesicle lipid mixing. Large alpha-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 alpha-Syn monomer has a negligible effect on lipid mixing even with a 30-fold excess compared with the case of large alpha-Syn oligomers. Thus, the results suggest that large alpha-Syn oligomers function as inhibitors of dopamine release, which thus provides a clue, at the molecular level, to their neurotoxicity. English NATL ACAD SCIENCES LEWY BODY DISEASE PARKINSONS-DISEASE SUBSTANTIA-NIGRA MEMBRANE-FUSION NEUROTRANSMITTER RELEASE PC12 CELLS IN-VITRO DOPAMINE PROTEIN NEUROMELANIN Large alpha-synuclein oligomers inhibit neuronal SNARE-mediated vesicle docking Article 10.1073/pnas.1218424110 1 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v.110, no.10, pp.4087 - 4092 PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA 110 10 4087 4092 scie scopus 000316377400085 2-s2.0-84874611934 Multidisciplinary Sciences Science & Technology - Other Topics Article LEWY BODY DISEASE PARKINSONS-DISEASE SUBSTANTIA-NIGRA MEMBRANE-FUSION NEUROTRANSMITTER RELEASE PC12 CELLS IN-VITRO DOPAMINE PROTEIN NEUROMELANIN exocytosis neuroscience vesicle fusion alternating-laser excitation single-vesicle