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.
| Original language | English |
|---|---|
| Article number | 10422 |
| Journal | Scientific Reports |
| Volume | 5 |
| Pages (from-to) | 1-12 |
| Number of pages | 12 |
| ISSN | 2045-2322 |
| DOIs | |
| Publication status | Published - 28 May 2015 |
Keywords
- Alzheimer Disease
- Amyloid
- Amyloidogenic Proteins
- Humans
- Ligands
- Parkinson Disease
- Protein Aggregation, Pathological
- Protein Structure, Secondary
- Pyridones
- alpha-Synuclein