Distinct higher-order alpha-synuclein oligomers induce intracellular aggretation

ILLES-TOTH, Eva, RAMOS, Mafalda, CAPPAI, Roberto, DALTON, Caroline and SMITH, David (2015). Distinct higher-order alpha-synuclein oligomers induce intracellular aggretation. Biochemical Journal, 468 (3), 485-493.

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Misfolding and aggregation of alpha-synuclein (α-syn) into Lewy bodies (LB) 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 preceded LB formation. Oligomers produced in vitro under certain conditions have been demonstrated to induce intracellular aggregation in cell culture models. Here we characterize, by electrospray ionisation - ion mobility spectrometry - mass spectrometry (ESI-IMS-MS), a specific population of α-syn oligomers. These mass spectrometry 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 mass spectrometry 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.

Item Type: Article
Research Institute, Centre or Group: Biomolecular Sciences Research Centre
Identification Number: 10.1042/BJ20150159
Depositing User: Marguerite Lyons
Date Deposited: 24 Jun 2015 11:21
Last Modified: 02 Oct 2015 11:10
URI: http://shura.shu.ac.uk/id/eprint/10364

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