title: EGCG remodels mature alpha-synuclein and amyloid-beta fibrils and reduces cellular toxicity.
abstract: 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.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Robert-Roessle-Strasse 10, 13125 Berlin-Buch, Germany. jbiesch@mdc-berlin.de
authors.forename: Jan
authors.initials: J
authors.lastname: Bieschke
authors.forename: Jenny
authors.initials: J
authors.lastname: Russ
authors.forename: Ralf P
authors.initials: RP
authors.lastname: Friedrich
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.forename: Heike
authors.initials: H
authors.lastname: Wobst
authors.forename: Katja
authors.initials: K
authors.lastname: Neugebauer
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
mesh_terms: 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*
chemical_list: D000682:Amyloid; D016229:Amyloid beta-Peptides; D018696:Neuroprotective Agents; D051844:alpha-Synuclein; D002392:Catechin; C045651:epigallocatechin gallate
references.citation: J Biol Chem. 2003 Jan 31;278(5):3235-40
references.pmid: 12435752
references.citation: Blood. 2007 Sep 15;110(6):2216
references.pmid: 17785589
references.citation: J Neurochem. 1996 Nov;67(5):2074-8
references.pmid: 8863516
references.citation: Hum Mol Genet. 2006 Sep 15;15(18):2743-51
references.pmid: 16893904
references.citation: Hum Mol Genet. 2002 Nov 1;11(23):2905-17
references.pmid: 12393802
references.citation: J Biol Chem. 2004 Jun 25;279(26):26846-57
references.pmid: 15096521
references.citation: Nat Chem Biol. 2009 Dec;5(12):936-46
references.pmid: 19915541
references.citation: Nat Med. 1998 Jul;4(7):822-6
references.pmid: 9662374
references.citation: Nature. 2003 Dec 18;426(6968):905-9
references.pmid: 14685252
references.citation: J Biol Chem. 2005 Feb 18;280(7):5892-901
references.pmid: 15590663
references.citation: Proteins. 2006 Aug 1;64(2):355-62
references.pmid: 16705651
references.citation: Chirality. 2007 Aug;19(8):642-6
references.pmid: 17568427
references.citation: J Biol Chem. 1991 Jan 15;266(2):689-92
references.pmid: 1702437
references.citation: Nature. 2002 Apr 4;416(6880):535-9
references.pmid: 11932745
references.citation: Nat Struct Mol Biol. 2008 Jun;15(6):558-66
references.pmid: 18511942
references.citation: Nat Rev Mol Cell Biol. 2007 Feb;8(2):101-12
references.pmid: 17245412
references.citation: Methods Enzymol. 1999;309:375-86
references.pmid: 10507036
references.citation: PLoS Biol. 2004 Oct;2(10):e321
references.pmid: 15383837
references.citation: J Neurochem. 2008 Oct;107(1):218-29
references.pmid: 18691383
references.citation: Methods Enzymol. 1999;309:274-84
references.pmid: 10507030
references.citation: J Nutr. 2008 Aug;138(8):1578S-1583S
references.pmid: 18641210
references.citation: Science. 2006 Nov 3;314(5800):777-81
references.pmid: 17082447
references.citation: Proc Natl Acad Sci U S A. 2009 Jun 2;106(22):9033-8
references.pmid: 19451623
references.citation: Biochemistry. 2001 Sep 25;40(38):11604-13
references.pmid: 11560511
references.citation: J Biol Chem. 2003 Nov 21;278(47):47016-24
references.pmid: 12958308
references.citation: Cell. 1993 Jun 18;73(6):1055-8
references.pmid: 8513491
references.citation: Biochim Biophys Acta. 2008 Sep;1782(9):523-31
references.pmid: 18602001
references.citation: Proc Natl Acad Sci U S A. 2009 Nov 24;106(47):19813-8
references.pmid: 19843697
references.citation: Biochemistry. 2009 Sep 1;48(34):8206-24
references.pmid: 19634918