The Role of Stable 伪-Synuclein Oligomers in the Molecular Events Underlying Amyloid Formation
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- 作者：Nikolai Lorenzen ; S酶ren Bang Nielsen ; Alexander K. Buell ; J酶rn D酶vling Kaspersen ; Paolo Arosio ; Brian Stougaard Vad ; Wojciech Paslawski ; Gunna Christiansen ; Zuzana Valnickova-Hansen ; Maria Andreasen ; Jan J. Enghild ; Jan Skov Pedersen ; Christopher M. Dobson ; Tuomas P. J. Knowles ; Daniel Erik Otzen
- 刊名：Journal of the American Chemical Society
- 出版年：2014
- 出版时间：March 12, 2014
- 年：2014
- 卷：136
- 期：10
- 页码：3859-3868
- 全文大小：533K
- 年卷期：v.136,no.10(March 12, 2014)
- ISSN：1520-5126
文摘
Studies of proteins鈥?formation of amyloid fibrils have revealed that potentially cytotoxic oligomers frequently accumulate during fibril formation. An important question in the context of mechanistic studies of this process is whether or not oligomers are intermediates in the process of amyloid fibril formation, either as precursors of fibrils or as species involved in the fibril elongation process or instead if they are associated with an aggregation process that is distinct from that generating mature fibrils. Here we describe and characterize in detail two well-defined oligomeric species formed by the protein 伪-synuclein (伪SN), whose aggregation is strongly implicated in the development of Parkinson鈥檚 disease (PD). The two types of oligomers are both formed under conditions where amyloid fibril formation is observed but differ in molecular weight by an order of magnitude. Both possess a degree of 尾-sheet structure that is intermediate between that of the disordered monomer and the fully structured amyloid fibrils, and both have the capacity to permeabilize vesicles in vitro. The smaller oligomers, estimated to contain 30 monomers, are more numerous under the conditions used here than the larger ones, and small-angle X-ray scattering data suggest that they are ellipsoidal with a high degree of flexibility at the interface with solvent. This oligomer population is unable to elongate fibrils and indeed results in an inhibition of the kinetics of amyloid formation in a concentration-dependent manner.