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Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models

Item Type:Article
Title:Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models
Creators Name:Ehrnhoefer, D.E. and Duennwald, M. and Markovic, P. and Wacker, J.L. and Engemann, S. and Roark, M. and Legleiter, J. and Marsh, J.L. and Thompson, L.M. and Lindquist, S. and Muchowski, P.J. and Wanker, E.E.
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.
Keywords:Camellia sinensis, Catechin, Drosophila melanogaster, Exons, Huntington Disease, Atomic Force Microscopy, Biological Models, Motor Neurons, Multiprotein Complexes, Mutation, Nerve Degeneration, Nerve Tissue Proteins, Nuclear Proteins, Invertebrate Photoreceptors, Phytotherapy, Protein Conformation, Protein Folding, Quaternary Protein Structure, Recombinant Fusion Proteins, Saccharomyces cerevisiae, Animals, Insects
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:15
Number:18
Page Range:2743-2751
Date:15 September 2006
Official Publication:https://doi.org/10.1093/hmg/ddl210
PubMed:View item in PubMed

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