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EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers

Official URL:https://doi.org/10.1038/nsmb.1437
PubMed:View item in PubMed
Creators Name:Ehrnhoefer, D.E. and Bieschke, J. and Boeddrich, A. and Herbst, M. and Masino, L. and Lurz, R. and Engemann, S. and Pastore, A. and Wanker, E.E.
Journal Title:Nature Structural & Molecular Biology
Journal Abbreviation:Nat Struct Mol Biol
Volume:15
Number:6
Page Range:558-566
Date:June 2008
Keywords:Amyloid, Amyloid Neuropathies, Amyloid beta-Protein, Catechin, Peptide Fragments, Protein Binding, Senile Plaques, alpha-Synuclein
Abstract:The accumulation of beta-sheet-rich amyloid fibrils or aggregates is a complex, multistep process that is associated with cellular toxicity in a number of human protein misfolding disorders, including Parkinson's and Alzheimer's diseases. It involves the formation of various transient and intransient, on- and off-pathway aggregate species, whose structure, size and cellular toxicity are largely unclear. Here we demonstrate redirection of amyloid fibril formation through the action of a small molecule, resulting in off-pathway, highly stable oligomers. The polyphenol (-)-epigallocatechin gallate efficiently inhibits the fibrillogenesis of both alpha-synuclein and amyloid-beta by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of beta-sheet-rich amyloid, the formation of unstructured, nontoxic alpha-synuclein and amyloid-beta oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
ISSN:1545-9985
Publisher:Nature Publishing Group
Item Type:Article

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