title: Distinct higher-order α-synuclein oligomers induce intracellular aggregation.
abstract: Misfolding and aggregation of α-synuclein (α-syn) into Lewy bodies is associated with a range of neurological disorders, including Parkinson's disease (PD). The cell-to-cell transmission of α-syn pathology has been linked to soluble amyloid oligomer populations that precede Lewy body formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. In the present study, we characterize, by ESI-ion mobility spectrometry (IMS)-MS, a specific population of α-syn oligomers. These MS-compatible oligomers were compared with oligomers with known seeding and pore-forming capabilities and were shown to have the ability to induce intracellular aggregation. Each oligomer type was shown to have distinct epitope profiles that correlated with their toxic gain-of-function. Structurally, the MS compatible oligomers populated a range of species from dimers through to hexamers. Lower-order oligomers were structurally diverse and consistent with unstructured assemblies. Higher-order oligomers were shown to be compact with ring-like structures. The observation of this compact state may explain how this natively disordered protein is able to transfer pathology from cell to cell and avoid degradation by cellular proteases.
authors: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, U.K.
authors: Eva
authors: E
authors: Illes-Toth
authors: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, U.K.
authors: Mafalda Ribeiro
authors: MR
authors: Ramos
authors: Department of Pathology, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, Victoria 3010, Australia.
authors: Roberto
authors: R
authors: Cappai
authors: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, U.K.
authors: Caroline
authors: C
authors: Dalton
authors: Biomedical Research Centre, Sheffield Hallam University, Howard Street, Sheffield S1 1WB, U.K. d.p.smith@shu.ac.uk.
authors: David P
authors: DP
authors: Smith
mesh_terms: D020013:Calcium Signaling; D045744:Cell Line, Tumor; D002470:Cell Survival; D019295:Computational Biology / Q000379:methods; D005103:Expert Systems; D006801:Humans; D064267:Intrinsically Disordered Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008958:Models, Molecular; D008970:Molecular Weight; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D066263:Protein Aggregation, Pathological / Q000378:metabolism* / Q000473:pathology; D011487:Protein Conformation; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D021241:Spectrometry, Mass, Electrospray Ionization; D053719:Tandem Mass Spectrometry; D051844:alpha-Synuclein / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D064267:Intrinsically Disordered Proteins; D011994:Recombinant Proteins; C497604:SNCA protein, human; D051844:alpha-Synuclein
keywords: aggregation; amyloid; ion mobility; mass spectrometry (MS); oligomer; α-synuclein