Author:
Chen Serene W.,Drakulic Srdja,Deas Emma,Ouberai Myriam,Aprile Francesco A.,Arranz Rocío,Ness Samuel,Roodveldt Cintia,Guilliams Tim,De-Genst Erwin J.,Klenerman David,Wood Nicholas W.,Knowles Tuomas P.J.,Alfonso Carlos,Rivas Germán,Abramov Andrey Y.,Valpuesta José María,Dobson Christopher M.,Cremades Nunilo
Abstract
We describe the isolation and detailed structural characterization of stable toxic oligomers of α-synuclein that have accumulated during the process of amyloid formation. Our approach has allowed us to identify distinct subgroups of oligomers and to probe their molecular architectures by using cryo-electron microscopy (cryoEM) image reconstruction techniques. Although the oligomers exist in a range of sizes, with different extents and nature of β-sheet content and exposed hydrophobicity, they all possess a hollow cylindrical architecture with similarities to certain types of amyloid fibril, suggesting that the accumulation of at least some forms of amyloid oligomers is likely to be a consequence of very slow rates of rearrangement of their β-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the β-sheet geometry acquired in the early stages of the self-assembly process plays in dictating the kinetic stability and the pathological nature of individual oligomeric species.
Publisher
Proceedings of the National Academy of Sciences
Cited by
399 articles.
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