Structural characterization of toxic oligomers that are kinetically trapped during ?-synuclein fibril formation.

ABSTRACT: We describe the isolation and detailed structural characterization of stable toxic oligomers of ?-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 ?-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 ?-sheet structures. Our findings reveal the inherent multiplicity of the process of protein misfolding and the key role the ?-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.

SUBMITTER: Chen SW 

PROVIDER: S-EPMC4413268 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature