Chen…Cremades {PNAS 112: E1994}
Stable toxic α-synuclein oligomers of different sizes, β-sheet content and hydrophobicity can possess similar quaternary structure with remarkable similarities with amyloid fibrils. This suggests that the β-sheet geometry at incipient self-assembly can affect kinetic stability and toxicity
Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation
Chen SW, Drakulic S, Deas E, Ouberai M, Aprile FA, Arranz R, Ness S, Roodveldt C, Guilliams T, De-Genst EJ, Klenerman D, Wood NW, Knowles TP, Alfonso C, Rivas G, Abramov AY, Valpuesta JM, Dobson CM, Cremades N
Proc Natl Acad Sci USA. 2015 April; 112:E1994.
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.
PubMed: 25855634. Doi: 10.1073/pnas.1421204112
