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

Research output: Contribution to journalJournal articleResearchpeer-review

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 languageEnglish
Article number10422
JournalScientific Reports
Volume5
Pages (from-to)1-12
Number of pages12
ISSN2045-2322
DOIs
Publication statusPublished - 2015

    Research areas

  • Alzheimer Disease, Amyloid, Amyloidogenic Proteins, Humans, Ligands, Parkinson Disease, Protein Aggregation, Pathological, Protein Structure, Secondary, Pyridones, alpha-Synuclein

ID: 161863000