EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity.
Protein misfolding and formation of beta-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer's and Parkinson's disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits alpha-synuclein and amyloid-beta fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature alpha-synuclein and amyloid-beta fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to beta-sheet-rich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.
Bieschke
Jan
J
Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin-Buch, Germany. jbiesch@mdc-berlin.de
Russ
Jenny
J
Friedrich
Ralf P
RP
Ehrnhoefer
Dagmar E
DE
Wobst
Heike
H
Neugebauer
Katja
K
Wanker
Erich E
EE
D000682:Amyloid / Q000096:biosynthesis* / Q000187:drug effects; D017772:Amyloid Neuropathies / Q000188:drug therapy / Q000517:prevention & control*; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D015153:Blotting, Western; D016466:CHO Cells; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002846:Chromatography, Affinity; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D004926:Escherichia coli; D006801:Humans; D018625:Microscopy, Atomic Force; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016716:PC12 Cells; D051381:Rats; D051844:alpha-Synuclein / Q000378:metabolism*
D000682:Amyloid; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D002392:Catechin; C045651:epigallocatechin gallate
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