Ehrnhoefer, D.E. et al. Green tea (-)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models. Hum. Mol. Genet. 15, 2743-2751

Max Delbrueck Center for Molecular Medicine, Department of Neuroproteomics, Berlin, Germany.
Human Molecular Genetics (Impact Factor: 6.39). 10/2006; 15(18):2743-51. DOI: 10.1093/hmg/ddl210
Source: PubMed


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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Available from: Dagmar Elisabeth Ehrnhoefer, Oct 23, 2015
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    • "In addition, EGCG treatment has been reported to increase the expression of SOD and reduce ROS levels in C. elegans (Zhang et al. 2009). Furthermore, Huntington disease (HD)-related phenotypes such as photoreceptor degeneration and motor function were shown to improve when EGCG was fed to transgenic HD flies overexpressing a pathogenic htt exon 1 protein (Ehrnhoefer et al. 2006). Other studies have demonstrated the life spanextending effect of catechin using various animal models. "

    Full-text · Chapter · May 2015
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    • "There is a growing body of evidence to indicate that polyphenol compounds have the ability to convert large, mature α-synuclein, and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells [30–32]. Epigallocatechin gallate (EGCG) significantly reduces the aggregation and cytotoxicity of the Huntington protein containing polyglutamine (polyQ) in a yeast model of Huntington's disease [33]. It should also be noted that tea drinking has been shown to exert neuroprotective activities in a wide array of cellular and animal models of neurological disorders [34]. "
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    ABSTRACT: FET family proteins consist of fused in sarcoma/translocated in liposarcoma (FUS/TLS), Ewing's sarcoma (EWS), and TATA-binding protein-associated factor 15 (TAF15). Mutations in the copper/zinc superoxide dismutase (SOD1), TAR DNA-binding protein 43 (TDP-43), and FET family proteins are associated with the development of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease. There is currently no cure for this disease and few effective treatments are available. Epidemiological studies indicate that the consumption of tea is associated with a reduced risk of developing neurodegenerative diseases. The results of this study revealed that components of a pu-erh tea extract (PTE) interacted with FET family proteins but not with TDP-43 or SOD1. PTE induced the degradation of FET family proteins but had no effects on TDP-43 or SOD1. The most frequently occurring ALS-linked FUS/TLS mutant protein, R521C FUS/TLS, was also degraded in the presence of PTE. Furthermore, ammonium chloride, a lysosome inhibitor, but not lactacystin, a proteasome inhibitor, reduced the degradation of FUS/TLS protein by PTE. PTE significantly reduced the incorporation of R521C FUS/TLS into stress granules under stress conditions. These findings suggest that PTE may have beneficial health effects, including preventing the onset of FET family protein-associated neurodegenerative diseases and delaying the progression of ALS by inhibiting the cytoplasmic aggregation of FET family proteins.
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    • "Further investigation of the anti-aggregation activity showed that EGCG modulated or inhibited amyloid assembly of a number of amyloidogenic polypeptides, including amyloid β-protein (Aβ, related to AD), α-synuclein (related to PD), islet amyloid polypeptide (IAPP, also known as amylin, related to type-2 diabetes), Htt (related to Huntington's disease), the human immunodeficiency virus enhancer factor – semen-derived enhancer of virus infection (SEVI), and the Plasmodium falciparum merozoite surface protein 2 (related to malaria) [43] [56] [57] [58] [59] [60] [61] [62] [63]. EGCG also causes conversion of the cellular form of the prion protein, PrP C , into a form distinct from the pathological scrapie prion protein, PrP Sc [64]. "
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    ABSTRACT: Abnormal protein folding and self-assembly causes over 30 cureless human diseases for which no disease-modifying therapies are available. The common side to all these diseases is formation of aberrant toxic protein oligomers and amyloid fibrils. Both types of assemblies are drug targets, yet each presents major challenges to drug design, discovery, and development. In this review, we focus on two small molecules that inhibit formation of toxic amyloid protein assemblies - the green-tea derivative (-)-epigallocatechin-3-gallate (EGCG), which was identified through a combination of epidemiologic data and a compound library screen, and the molecular tweezer CLR01, whose inhibitory activity was discovered in our group based on rational reasoning, and subsequently confirmed experimentally. Both compounds act in a manner that is not specific to one particular protein and thus are useful against a multitude of amyloidogenic proteins, yet they act via distinct putative mechanisms. CLR01 disrupts protein aggregation through specific binding to lysine residues, whereas the mechanisms underlying the activity of EGCG are only recently beginning to unveil. We discuss current in vitro and, where available, in vivo literature related to EGCG and CLR01's effects on amyloid beta-protein, alpha-synuclein, transthyretin, islet amyloid polypeptide, and calcitonin. We also describe the toxicity, pharmacokinetics, and mechanism of action of each compound.
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