Open AccessEGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity
Author(s) -
Jan Bieschke,
Jenny Russ,
Ralf P. Friedrich,
Dagmar E. Ehrnhoefer,
Heike J. Wobst,
Katja Neugebauer,
Erich E. Wanker
Publication year - 2010
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0910723107
Subject(s) - fibrillogenesis , fibril , alpha synuclein , chemistry , amyloid (mycology) , protein folding , synucleinopathies , biophysics , protein aggregation , beta sheet , biochemistry , microbiology and biotechnology , protein structure , biology , parkinson's disease , medicine , inorganic chemistry , disease , pathology
Protein misfolding and formation of β-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 α-synuclein and amyloid-β 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 α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-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.