Article

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

Max Delbrueck Center for Molecular Medicine, Department of Neuroproteomics, Berlin, Germany.
Human Molecular Genetics (Impact Factor: 6.68). 10/2006; 15(18):2743-51. DOI: 10.1093/hmg/ddl210
Source: PubMed

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.

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