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
Amyloidogenic Proteins
alpha-Synuclein
chemistry
Ligands
Amyloid
chemistry
chemistry
metabolism
Parkinson Disease
pathology
Protein Aggregation
metabolism
metabolism
Humans
Protein Structure
metabolism
Secondary
metabolism
pathology
Pyridones
Pathological
metabolism
Alzheimer Disease
Author
Martin Nors Perdersen
University of Copenhagen
Vito Foderà
University of Copenhagen
Istvan Horvath
Umeå University
Andreas van Maarschalkerweerd
University of Copenhagen
Katrine Nørgaard Toft
University of Copenhagen
Christoph Weise
Umeå University
F. Almqvist
Umeå University
Magnus Wolf-Watz
Umeå University
Pernilla Wittung Stafshede
Umeå University
Bente Vestergaard
University of Copenhagen
Scientific Reports
2045-2322 (ISSN) 20452322 (eISSN)
Vol. 5 10422-Subject Categories
Biological Sciences
Biophysics
DOI
10.1038/srep10422
PubMed
26020724