Dagmar E Ehrnhoefer, Jan Bieschke, Annett Boeddrich, Martin Herbst, Laura Masino, Rudi Lurz, Sabine Engemann, Annalisa Pastore & Erich E Wanker
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-Straße 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.
Nature Structural & Molecular Biology 15, 558 – 566 (2008)
http://www.nature.com/nsmb/journal/v15/n6/abs/nsmb.1437.html