Article abstract
Nature Structural & Molecular Biology 15, 558 - 566 (2008)
Published online: 30 May 2008 | doi:10.1038/nsmb.1437
EGCG redirects amyloidogenic polypeptides into unstructured, off-pathway oligomers
Dagmar E Ehrnhoefer1,4, Jan Bieschke1,4, Annett Boeddrich1, Martin Herbst1, Laura Masino2, Rudi Lurz3, Sabine Engemann1, Annalisa Pastore2 & Erich E Wanker1
Abstract
The accumulation of 
-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 
-synuclein and amyloid- by directly binding to the natively unfolded polypeptides and preventing their conversion into toxic, on-pathway aggregation intermediates. Instead of -sheet–rich amyloid, the formation of unstructured, nontoxic -synuclein and amyloid- oligomers of a new type is promoted, suggesting a generic effect on aggregation pathways in neurodegenerative diseases.
-
Max Delbrueck Center for Molecular Medicine (MDC), AG Neuroproteomics, Robert-Roessle-Stra
e 10, 13092 Berlin, Germany. - National Institute for Medical Research (NIMR), The Ridgeway, Mill Hill, London NW7 1AA, UK.
- Max Planck Institute for Molecular Genetics, Ihnestrasse 73, 14195 Berlin, Germany.
- These authors contributed equally to the work.
Correspondence to: Erich E Wanker1 e-mail: ewanker@mdc-berlin.de
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