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- Title
EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.
- Authors
Ehrnhoefer, Dagmar E; Bieschke, Jan; Boeddrich, Annett; Herbst, Martin; Masino, Laura; Lurz, Rudi; Engemann, Sabine; Pastore, Annalisa; Wanker, Erich E
- 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.
- Publication
Nature structural & molecular biology, 2008, Vol 15, Issue 6, p558
- ISSN
1545-9985
- Publication type
Journal Article
- DOI
10.1038/nsmb.1437