Direct correlation between ligand-induced α-synuclein oligomers and amyloid-like fibril growth

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Abstract

Aggregation of proteins into amyloid deposits is the hallmark of several neurodegenerative diseases such as Alzheimer' s and Parkinson' s disease. The suggestion that intermediate oligomeric species may be cytotoxic has led to intensified investigations of pre-fibrillar oligomers, which are complicated by their transient nature and low population. Here we investigate alpha-synuclein oligomers, enriched by a 2-pyridone molecule (FN075), and the conversion of oligomers into fibrils. As probed by leakage assays, the FN075 induced oligomers potently disrupt vesicles in vitro, suggesting a potential link to disease related degenerative activity. Fibrils formed in the presence and absence of FN075 are indistinguishable on microscopic and macroscopic levels. Using small angle X-ray scattering, we reveal that FN075 induced oligomers are similar, but not identical, to oligomers previously observed during alpha-synuclein fibrillation. Since the levels of FN075 induced oligomers correlate with the amounts of fibrils among different FN075:protein ratios, the oligomers appear to be on-pathway and modeling supports an 'oligomer stacking model' for alpha-synuclein fibril elongation.

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Nors Perdersen, M., Foderà, V., Horvath, I., Van Maarschalkerweerd, A., Nørgaard Toft, K., Weise, C., … Vestergaard, B. (2015). Direct correlation between ligand-induced α-synuclein oligomers and amyloid-like fibril growth. Scientific Reports, 5. https://doi.org/10.1038/srep10422

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