Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth

• DOI: 10.1038/srep10422
• Publication Date: 2015-05-28T13:30:50Z
• Authors: Martin Nors Pedersen; Vito Foderà; Istvan Horvath; Andreas van Maars...; Katrine Nørgaard ...; Christoph Weise; Fredrik Almqvist; Magnus Wolf-Watz; Pernilla Wittung-...; Bente Vestergaard
• Keywords: Oligomer; Amyloid (mycology)

Abstract Aggregation of proteins into amyloid deposits is the hallmark 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 pre-fibrillar oligomers, which are complicated by their transient nature low population. Here we investigate alpha-synuclein enriched a 2-pyridone molecule (FN075) conversion oligomers fibrils. As probed leakage assays, FN075 induced potently disrupt vesicles in vitro, suggesting potential link disease related degenerative activity. Fibrils formed presence absence indistinguishable on microscopic macroscopic levels. Using small angle X-ray scattering, reveal similar, but not identical, previously observed during fibrillation. Since levels correlate with amounts fibrils among different FN075:protein ratios, appear on-pathway modeling supports an ‘oligomer stacking model’ for fibril elongation.