title: Low-resolution structure of a vesicle disrupting &alpha;-synuclein oligomer that accumulates during fibrillation.
abstract: One of the major hallmarks of Parkinson disease is aggregation of the protein α-synuclein (αSN). Aggregate cytotoxicity has been linked to an oligomeric species formed at early stages in the aggregation process. Here we follow the fibrillation process of αSN in solution over time using small angle X-ray scattering and resolve four major coexisting species in the fibrillation process, namely monomer, dimer, fibril and an oligomer. By ab initio modeling to fit the data, we obtain a low-resolution structure of a symmetrical and slender αSN fibril in solution, consisting of a repeating unit with a maximal distance of 900 Å and a diameter of ∼180 Å. The same approach shows the oligomer to be shaped like a wreath, with a central channel and with dimensions corresponding to the width of the fibril. The structure, accumulation and decay of this oligomer is consistent with an on-pathway role for the oligomer in the fibrillation process. We propose an oligomer-driven αSN fibril formation mechanism, where the fibril is built from the oligomers. The wreath-shaped structure of the oligomer highlights its potential cytotoxicity by simple membrane permeabilization. This is confirmed by the ability of the purified oligomer to disrupt liposomes. Our results provide the first structural description in solution of a potentially cytotoxic oligomer, which accumulates during the fibrillation of αSN.
authors.affiliation: Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark.
authors.forename: Lise
authors.initials: L
authors.lastname: Giehm
authors.forename: Dmitri I
authors.initials: DI
authors.lastname: Svergun
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Otzen
authors.forename: Bente
authors.initials: B
authors.lastname: Vestergaard
mesh_terms: D002463:Cell Membrane Permeability; D006801:Humans; D008081:Liposomes / Q000378:metabolism; D010300:Parkinson Disease / Q000473:pathology; D011487:Protein Conformation; D055503:Protein Multimerization; D014961:X-Ray Diffraction; D051844:alpha-Synuclein / Q000737:chemistry* / Q000633:toxicity
chemical_list: D008081:Liposomes; D051844:alpha-Synuclein