title: Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models.
abstract: Huntington's disease (HD) is a progressive neurodegenerative disorder for which only symptomatic treatments of limited effectiveness are available. Preventing early misfolding steps and thereby aggregation of the polyglutamine (polyQ)-containing protein huntingtin (htt) in neurons of patients may represent an attractive therapeutic strategy to postpone the onset and progression of HD. Here, we demonstrate that the green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) potently inhibits the aggregation of mutant htt exon 1 protein in a dose-dependent manner. Dot-blot assays and atomic force microscopy studies revealed that EGCG modulates misfolding and oligomerization of mutant htt exon 1 protein in vitro, indicating that it interferes with very early events in the aggregation process. Also, EGCG significantly reduced polyQ-mediated htt protein aggregation and cytotoxicity in an yeast model of HD. When EGCG was fed to transgenic HD flies overexpressing a pathogenic htt exon 1 protein, photoreceptor degeneration and motor function improved. These results indicate that modulators of htt exon 1 misfolding and oligomerization like EGCG are likely to reduce polyQ-mediated toxicity in vivo. Our studies may provide the basis for the development of a novel pharmacotherapy for HD and related polyQ disorders.
authors.affiliation: Max Delbrueck Center for Molecular Medicine, Department of Neuroproteomics, Berlin, Germany.
authors.forename: Dagmar E
authors.initials: DE
authors.lastname: Ehrnhoefer
authors.forename: Martin
authors.initials: M
authors.lastname: Duennwald
authors.forename: Phoebe
authors.initials: P
authors.lastname: Markovic
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Wacker
authors.forename: Sabine
authors.initials: S
authors.lastname: Engemann
authors.forename: Margaret
authors.initials: M
authors.lastname: Roark
authors.forename: Justin
authors.initials: J
authors.lastname: Legleiter
authors.forename: J Lawrence
authors.initials: JL
authors.lastname: Marsh
authors.forename: Leslie M
authors.initials: LM
authors.lastname: Thompson
authors.forename: Susan
authors.initials: S
authors.lastname: Lindquist
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Muchowski
authors.forename: Erich E
authors.initials: EE
authors.lastname: Wanker
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D028241:Camellia sinensis / Q000737:chemistry; D002392:Catechin / Q000031:analogs & derivatives* / Q000494:pharmacology; D004331:Drosophila melanogaster / Q000235:genetics; D005091:Exons; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D066298:In Vitro Techniques; D018625:Microscopy, Atomic Force; D008954:Models, Biological; D009046:Motor Neurons / Q000187:drug effects; D046912:Multiprotein Complexes; D009154:Mutation; D009410:Nerve Degeneration / Q000188:drug therapy; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D009687:Nuclear Proteins / Q000737:chemistry* / Q000187:drug effects* / Q000235:genetics; D017956:Photoreceptor Cells, Invertebrate / Q000187:drug effects; D008517:Phytotherapy; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000737:chemistry / Q000187:drug effects / Q000235:genetics
chemical_list: C086055:HTT protein, human; D000071058:Huntingtin Protein; D046912:Multiprotein Complexes; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D011993:Recombinant Fusion Proteins; D002392:Catechin; C045651:epigallocatechin gallate