Direct Correlation Between Ligand-Induced α-Synuclein Oligomers and Amyloid-like Fibril Growth.
Artikel i vetenskaplig tidskrift, 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

Författare

Martin Nors Perdersen

Köpenhamns universitet

Vito Foderà

Köpenhamns universitet

Istvan Horvath

Umeå universitet

Andreas van Maarschalkerweerd

Köpenhamns universitet

Katrine Nørgaard Toft

Köpenhamns universitet

Christoph Weise

Umeå universitet

F. Almqvist

Umeå universitet

Magnus Wolf-Watz

Umeå universitet

Pernilla Wittung Stafshede

Umeå universitet

Bente Vestergaard

Köpenhamns universitet

Scientific Reports

2045-2322 (ISSN)

Vol. 5 10422-

Ämneskategorier

Biologiska vetenskaper

Biofysik

DOI

10.1038/srep10422

PubMed

26020724

Mer information

Senast uppdaterat

2019-06-12