Molecules and Cells

  • 제45권11호
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  • Pages.806-819
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  • 2022
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  • 1016-8478(pISSN)
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  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
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α-Synuclein Disrupts Vesicle Fusion by Two Mutant-Specific Mechanisms

  • Yoo, Gyeongji (Department of Chemistry, Seoul National University) ;
  • An, Hyeong Jeon (Department of Physics, Pohang University of Science and Technology) ;
  • Yeou, Sanghun (Department of Chemistry, Seoul National University) ;
  • Lee, Nam Ki (Department of Chemistry, Seoul National University)
  • 투고 : 2022.06.23
  • 심사 : 2022.07.28
  • 발행 : 2022.11.30
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초록

Synaptic accumulation of α-synuclein (α-Syn) oligomers and their interactions with VAMP2 have been reported to be the basis of synaptic dysfunction in Parkinson's disease (PD). α-Syn mutants associated with familial PD have also been known to be capable of interacting with VAMP2, but the exact mechanisms resulting from those interactions to eventual synaptic dysfunction are still unclear. Here, we investigate the effect of α-Syn mutant oligomers comprising A30P, E46K, and A53T on VAMP2-embedded vesicles. Specifically, A30P and A53T oligomers cluster vesicles in the presence of VAMP2, which is a shared mechanism with wild type α-Syn oligomers induced by dopamine. On the other hand, E46K oligomers reduce the membrane mobility of the planar bilayers, as revealed by single-particle tracking, and permeabilize the membranes in the presence of VAMP2. In the absence of VAMP2 interactions, E46K oligomers enlarge vesicles by fusing with one another. Our results clearly demonstrate that α-Syn mutant oligomers have aberrant effects on VAMP2-embedded vesicles and the disruption types are distinct depending on the mutant types. This work may provide one of the possible clues to explain the α-Syn mutant-type dependent pathological heterogeneity of familial PD.

키워드

과제정보

This work was supported by the Creative-Pioneering Researchers Program of Seoul National University, NRF-2019R1A2C2090896, and NRF-2020R1A5A1019141 of the National Research Foundation of Korea.

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