한빛사 논문
Abstract
Bong-Kyu Choia,1, Mal-Gi Choib,1, Jae-Yeol Kimc,1, Yoosoo Yangb,d, Ying Laie, Dae-Hyuk Kweond, Nam Ki Leea,c,2, and Yeon-Kyun Shinb,e,2
aSchool of Interdisciplinary Bioscience and Bioengineering, and
cDepartment of Physics, Pohang University of Science and Technology, Pohang 790-784, Korea;
bBiomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, Korea;
dDepartment of Genetic Engineering, College of Biotechnology and Bioengineering, Sungkyunkwan University, Suwon 440-746, Korea; and
eDepartment of Biochemistry, Biophysics, and Molecular Biology, Iowa State University, Ames, IA 50011
Edited by William T. Wickner, Dartmouth Medical School, Hanover, NH, and approved December 6, 2012 (received for review October 23, 2012)
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.
exocytosis, neuroscience, vesicle fusion, alternating-laser excitation, single-vesicle
Footnotes
1B.-K.C., M.-G.C., and J.-Y.K. contributed equally to this work.
2To whom correspondence may be addressed.
Author contributions: N.K.L., and Y.-K.S. designed research; B.-K.C., M.-G.C., J.-Y.K., and Y.Y. performed research; Y.L. and D.-H.K. contributed new reagents/analytic tools; B.-K.C., M.-G.C., J.-Y.K., Y.Y., and D.-H.K. analyzed data; and N.K.L. and Y.-K.S. wrote the paper.
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