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Human Molecular Genetics Advance Access originally published online on August 7, 2006
Human Molecular Genetics 2006 15(18):2743-2751; doi:10.1093/hmg/ddl210
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

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

Dagmar E. Ehrnhoefer1, Martin Duennwald2, Phoebe Markovic1, Jennifer L. Wacker3, Sabine Engemann1, Margaret Roark5, Justin Legleiter3,4, J. Lawrence Marsh5, Leslie M. Thompson6, Susan Lindquist2, Paul J. Muchowski3,4 and Erich E. Wanker1,*

1 Max Delbrueck Center for Molecular Medicine (MDC), Department of Neuroproteomics, Robert-Roessle-Straße 10, 13092 Berlin, Germany, 2 Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, MA 02142, UK, 3 Department of Pharmacology, University of Washington, Seattle, WA 98195-7280, USA, 4 Gladstone Institute of Neurological Disease, and Departments of Biochemistry and Biophysics, and Neurology, University of California, San Francisco, CA 94158, USA, 5 Department of Developmental and Cell Biology and 6 Departments of Psychiatry and Human Behavior and Biological Chemistry, University of California, Irvine, CA 92697, USA

* To whom correspondence should be addressed. Tel: +49 30 9406 2157; Fax: +49 30 9406 2552; Email: ewanker{at}mdc-berlin.de

Received May 16, 2006; Accepted July 31, 2006

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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