Green tea (−)-epigallocatechin-gallate modulates early events in huntingtin misfolding and reduces toxicity in Huntington's disease models
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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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.12/2013; 4(4-4):385-409. DOI:10.2478/s13380-013-0137-y
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ABSTRACT: Prion diseases are a group of fatal neurodegenerative diseases caused by the misfolding of cellular prion protein (PrPC) into pathogenic conformers (PrPSc). Although no effective therapies for prion diseases are currently available, a number of small molecule inhibitors have been identified that are capable of reducing or eliminating PrPSc in prion infected cells. However, recent experiments have shown that upon sustained treatment, prions have the capacity to evolve into drug resistant conformations. These studies suggest that the mechanism of prion strain adaptation involves rare conformational conversions followed by competitive selection among the heterogeneous pool of PrPSc conformers. The plasticity of prion conformers makes PrPSc a particularly challenging drug target and suggests that combination drug therapies or targeting of PrPC may be required for effective therapy. In this review, we highlight recent literature that demonstrate the phenomenon of prion drug resistance and strain specificity, and discuss potential ramifications for therapeutic efforts against prion diseases.Current topics in medicinal chemistry 09/2013; DOI:10.2174/15680266113136660168 · 3.45 Impact Factor
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ABSTRACT: Several neurodegenerative diseases, such as Parkinson's disease (PD), Alzheimer's disease (AD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), or prion diseases, are known for their intimate association with protein misfolding and aggregation. These disorders are characterized by the loss of specific neuronal populations in the brain and are highly associated with aging, suggesting a decline in proteostasis capacity may contribute to pathogenesis. Nevertheless, the precise molecular mechanisms that lead to the selective demise of neurons remain poorly understood. As a consequence, appropriate therapeutic approaches and effective treatments are largely lacking. The development of cellular and animal models that faithfully reproduce central aspects of neurodegeneration have been crucial for advancing our understanding of these diseases. Approaches involving the sequential use of different model systems, starting with simpler cellular models and ending with validation in more complex animal models, resulted in the discovery of promising therapeutic targets and small molecules with therapeutic potential. Within this framework, the simple and well-characterized eukaryote Saccharomyces cerevisiae, also known as budding yeast, is being increasingly used to study the molecular basis of several neurodegenerative disorders. Yeast provides an unprecedented toolbox for the dissection of complex biological processes and pathways. Here, we summarize how yeast models are adding to our current understanding of several neurodegenerative disorders. This article is protected by copyright. All rights reserved.Journal of Neurochemistry 04/2013; 127(4). DOI:10.1111/jnc.12271 · 4.24 Impact Factor