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Nat Struct Mol Biol. 2008 Jun;15(6):558-66. doi: 10.1038/nsmb.1437. Epub 2008 May 30.

EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers.

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  • 1Max Delbrueck Center for Molecular Medicine, AG Neuroproteomics, 13092 Berlin, Germany.

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.

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PMID:
18511942
DOI:
10.1038/nsmb.1437
[PubMed - indexed for MEDLINE]
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