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Sclerotiorin stabilizes the assembly of nonfibrillar Abeta42 oligomers with low toxicity, seeding activity, and beta-sheet content

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Item Type:Article
Title:Sclerotiorin stabilizes the assembly of nonfibrillar Abeta42 oligomers with low toxicity, seeding activity, and beta-sheet content
Creators Name:Wiglenda, T. and Groenke, N. and Hoffmann, W. and Manz, C. and Diez, L. and Buntru, A. and Brusendorf, L. and Neuendorf, N. and Schnoegl, S. and Haenig, C. and Schmieder, P. and Pagel, K. and Wanker, E.E.
Abstract:The self-assembly of the 42-residue amyloid-β peptide, Aβ42, into fibrillar aggregates is associated with neuronal dysfunction and toxicity in Alzheimer's disease (AD) patient brains, suggesting that small molecules acting on this process might interfere with pathogenesis. Here, we present experimental evidence that the small molecule sclerotiorin (SCL), a natural product belonging to the group of azaphilones, potently delays both seeded and non-seeded Aβ42 polymerization in cell-free assays. Mechanistic biochemical studies revealed that the inhibitory effect of SCL on fibrillogenesis is caused by its ability to kinetically stabilize small Aβ42 oligomers. These structures exhibit low β-sheet content and do not possess seeding activity, indicating that SCL acts very early in the amyloid formation cascade before the assembly of seeding-competent, β-sheet-rich fibrillar aggregates. Investigations with NMR WaterLOGSY experiments confirmed the association of Aβ42 assemblies with SCL in solution. Furthermore, using ion mobility-mass spectrometry we observed that SCL directly interacts with a small fraction of Aβ42 monomers in the gas phase. In comparison to typical amyloid fibrils, small SCL-stabilized Aβ42 assemblies are inefficiently taken up into mammalian cells and have low toxicity in cell-based assays. Overall, these mechanistic studies support a pathological role of stable, β-sheet-rich Aβ42 fibrils in AD, while structures with low β-sheet content may be less relevant.
Keywords:Biochemistry, Protein Aggregation, Small Molecules, NMR WaterLOGSY, Mass Spectrometry, Animals, Mice, Rats
Source:Journal of Molecular Biology
ISSN:0022-2836
Publisher:Elsevier
Volume:432
Number:7
Page Range:2080-2098
Date:27 March 2020
Official Publication:https://doi.org/10.1016/j.jmb.2020.01.033
PubMed:View item in PubMed

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