文章基本信息

标题：Low-resolution structure of a vesicle disrupting α-synuclein oligomer that accumulates during fibrillation
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作者：Lise Giehm ; Dmitri I. Svergun ; Daniel E. Otzen 等
期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2011
卷号：108
期号：8
页码：3246-3251
DOI：10.1073/pnas.1013225108
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：One of the major hallmarks of Parkinson disease is aggregation of the protein [α]-synuclein ([α]SN). Aggregate cytotoxicity has been linked to an oligomeric species formed at early stages in the aggregation process. Here we follow the fibrillation process of [α]SN in solution over time using small angle X-ray scattering and resolve four major coexisting species in the fibrillation process, namely monomer, dimer, fibril and an oligomer. By ab initio modeling to fit the data, we obtain a low-resolution structure of a symmetrical and slender [α]SN fibril in solution, consisting of a repeating unit with a maximal distance of 900 A and a diameter of [~]180 A. The same approach shows the oligomer to be shaped like a wreath, with a central channel and with dimensions corresponding to the width of the fibril. The structure, accumulation and decay of this oligomer is consistent with an on-pathway role for the oligomer in the fibrillation process. We propose an oligomer-driven [α]SN fibril formation mechanism, where the fibril is built from the oligomers. The wreath-shaped structure of the oligomer highlights its potential cytotoxicity by simple membrane permeabilization. This is confirmed by the ability of the purified oligomer to disrupt liposomes. Our results provide the first structural description in solution of a potentially cytotoxic oligomer, which accumulates during the fibrillation of [α]SN.
关键词：alpha-synuclein ; amyloid ; structral nucleus ; solution structure