Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth.
Journal article, 2015
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.
metabolism
metabolism
metabolism
Humans
chemistry
Alzheimer Disease
Protein Aggregation
Amyloidogenic Proteins
pathology
pathology
chemistry
Secondary
metabolism
metabolism
alpha-Synuclein
Ligands
Protein Structure
chemistry
metabolism
Parkinson Disease
Amyloid
metabolism
Pyridones
Pathological
Author
Martin Nors Perdersen
Vito Foderà
Istvan Horvath
Chalmers, Biology and Biological Engineering, Chemical Biology
Andreas van Maarschalkerweerd
Katrine Nørgaard Toft
Christoph Weise
F. Almqvist
Magnus Wolf-Watz
Pernilla Wittung Stafshede
Chalmers, Biology and Biological Engineering, Chemical Biology
Bente Vestergaard
Scientific Reports
2045-2322 (ISSN)
Vol. 5 10422-Subject Categories (SSIF 2011)
Biological Sciences
Biophysics
DOI
10.1038/srep10422
PubMed
26020724