Green Tea Extract Slows the Progression of Huntington’s Disease

A new study conducted in vitro and in fruit flies indicates that the green tea polyphenol, epigallocatechin gallate (EGCG), may slow the build up of proteins that are implicated in Huntington’s disease and may slow the motor function decline that occurs in Huntington’s patients.

Huntington's disease is a progressive neurodegenerative disorder for which only symptomatic treatments of limited effectiveness are available. Early symptoms of Huntington's Disease may affect cognitive ability or mobility and include depression, mood swings, forgetfulness, clumsiness, involuntary twitching and lack of coordination. As the disease progresses, concentration and short-term memory diminish and involuntary movements of the head, trunk and limbs increase. Walking, speaking and swallowing abilities deteriorate. Eventually the person is unable to care for him or herself.

Huntington’s is a hereditary disease and scientists have discovered the gene that causes proteins to mutate into the huntingtin protein. A mutation in this protein results in elongation of parts of the protein called polyglutamine chains, which cause the overall huntingtin protein to lose its normal structure. The body will not expel these mutant proteins and consequently they build up in the brain, where they are ultimately lethal to nerve cells.

Once the disease has developed it is incurable, so stopping the buildup of damaging proteins as well as stopping the proteins from misfolding could slow or prevent the development of the disease. As of the publication of this preliminary study, the Huntington's Disease Society of America website indicated that "Research has yet to find a means of curing or even slowing the deadly progression of HD although some medications can relieve some of the symptoms in certain individuals."

In the new study, scientists investigated the effects of EGCG from green tea on the aggregation of these mutant proteins in vitro. The study authors discovered that the green tea extract could strongly interfere with the early events leading up to the buildup of mutant proteins in a dose-dependent manner. In vitro, the green tea extract was able to inhibit the misfolding of the proteins.

As part of the same study, the researchers used fruit flies genetically modified to over-express the mutant protein, which served as a model for the hereditary disease. When the green tea extract was fed to the flies, photoreceptor degeneration and motor function improved.

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.

Source

Ehrnhoefer DE, Duennwald M, Markovic P, Wacker JL, Engemann S, Roark M, Legleiter J, Marsh JL, Thompson LM, Lindquist S, Muchowski PJ, Wanker EE. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum Mol Genet. 2006 Sep 15;15(18):2743-51. Epub 2006 Aug 7.

Key concepts: Green tea, EGCG, Huntington's Disease