title: Structural characterization of toxic oligomers that are kinetically trapped during α-synuclein fibril formation.
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.
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Serene W
authors: SW
authors: Chen
authors: Department of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain;
authors: Srdja
authors: S
authors: Drakulic
authors: Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;
authors: Emma
authors: E
authors: Deas
authors: Nanoscience Centre, Department of Engineering, University of Cambridge, Cambridge CB3 0FF, United Kingdom;
authors: Myriam
authors: M
authors: Ouberai
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Francesco A
authors: FA
authors: Aprile
authors: Department of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain;
authors: Rocío
authors: R
authors: Arranz
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Samuel
authors: S
authors: Ness
authors: Department of Cellular Therapy and Regenerative Medicine, Andalusian Center for Molecular Biology and Regenerative Medicine, 41092 Seville, Spain; and.
authors: Cintia
authors: C
authors: Roodveldt
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Tim
authors: T
authors: Guilliams
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Erwin J
authors: EJ
authors: De-Genst
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: David
authors: D
authors: Klenerman
authors: Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;
authors: Nicholas W
authors: NW
authors: Wood
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom;
authors: Tuomas P J
authors: TP
authors: Knowles
authors: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CIB-CSIC), 28040 Madrid, Spain.
authors: Carlos
authors: C
authors: Alfonso
authors: Department of Cellular and Molecular Biology, Centro de Investigaciones Biológicas (CIB-CSIC), 28040 Madrid, Spain.
authors: Germán
authors: G
authors: Rivas
authors: Department of Molecular Neuroscience, University College London, Institute of Neurology, London WC1N 3BG, United Kingdom;
authors: Andrey Y
authors: AY
authors: Abramov
authors: Department of Macromolecular Structure, Centro Nacional de Biotecnología (CNB-CSIC), 28049 Madrid, Spain;
authors: José María
authors: JM
authors: Valpuesta
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; nc347@cam.ac.uk cmd44@cam.ac.uk.
authors: Christopher M
authors: CM
authors: Dobson
authors: Department of Chemistry, University of Cambridge, Cambridge CB2 1EW, United Kingdom; nc347@cam.ac.uk cmd44@cam.ac.uk.
authors: Nunilo
authors: N
authors: Cremades
mesh_terms: D000682:Amyloid / Q000737:chemistry*; D020285:Cryoelectron Microscopy; D057927:Hydrophobic and Hydrophilic Interactions; D021621:Imaging, Three-Dimensional; D008958:Models, Molecular; D008970:Molecular Weight; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D051844:alpha-Synuclein / Q000737:chemistry* / Q000633:toxicity* / Q000648:ultrastructure
chemical_list: D000682:Amyloid; D051844:alpha-Synuclein
keywords: amyloid aggregation; cryoelectron microscopy; neurodegeneration; protein misfolding; toxic oligomer