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

Ehrnhoefer, Dagmar E.; Duennwald, Martin L.; Markovic, Phoebe; Wacker, Jennifer L.; Engemann, Sabine; Roark, Margaret; Legleiter, Justin; Marsh, J. Lawrence; Thompson, Leslie M.; Lindquist, Susan; Muchowski, Paul J.; Wanker, Erich E.

doi:10.1093/hmg/ddl210

Cited by 354 publications

(320 citation statements)

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“…In particular, disorder-to-order transitions upon EGCG binding have been observed for the human salivary proline-rich protein IB5 41 and the dephosphorylated form of -casein 42 . Moreover, EGCG has been shown to affect the aggregation pathway of several amyloidogenic proteins 4,[6][7][8] . These studies also suggest that EGCG binds to the protein backbone, as well as to hydrophilic and hydrophobic side chains.…”

Section: Resultsmentioning

confidence: 99%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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The intrinsically disordered and amyloidogenic protein -synuclein (AS) has been linked to several neurodegenerative states, including Parkinson's disease. Here, nano-electrospray-ionization mass spectrometry (nano-ESI-MS), ion mobility (IM), and native top-down electron transfer dissociation (ETD) techniques are employed to study AS interaction with small molecules known to modulate its aggregation, such as epigallocatechin-3-gallate (EGCG) and dopamine (DA). The complexes formed by the two ligands under identical conditions reveal peculiar differences. While EGCG engages AS in compact conformations, DA preferentially binds to the protein in partially extended conformations. The two ligands also have different effects on AS structure as assessed by IM, with EGCG leading to protein compaction and DA to its extension. Native top-down ETD on the protein-ligand complexes shows how the different observed modes of binding of the two ligands could be related to their known opposite effects on AS aggregation. The results also show that the protein can bind either ligand in the absence of any covalent modifications, such as e.g. oxidation.

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Section: Resultsmentioning

confidence: 99%

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

et al. 2016

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“…Rather, it promotes the formation of amorphous HTTex1 protein aggregates which are not observed in the absence of the substance [43]. This indicates that EGCG redirects the polyQ-mediated HTTex1 aggregation pathway, leading to the formation of a new type of aggregate structure.…”

Section: Identification Of Small Molecules That Influence Polyq-mediamentioning

confidence: 93%

“…3B). In EGCG treated flies, however, neurodegeneraton was significantly diminished, indicating that the compound has a protective effect on neurotoxicity in transgenic flies [43]. Intriguingly, EGCG is also a potent inhibitor of α-synuclein and amyloid-β fibrillogenesis, suggesting that it is a generic modulator of protein misfolding and aggregation [44].…”

Section: Identification Of Small Molecules That Influence Polyq-mediamentioning

confidence: 99%

“…Besides small molecule promoters of functional proteostasis, compounds that directly target the aggregation process have been identified. They include substances such as Congo red, Thioflavine S, PGL-135 or EGCG ((-)-epigallocatechin-3-gallate), which reduce the formation of polyQ-containing HTTex1 aggregates [41][42][43]. To date, the mode of action of EGCG has been studied most extensively (Fig.…”

Section: Identification Of Small Molecules That Influence Polyq-mediamentioning

confidence: 99%

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Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Trepte

Strempel

Wanker

2014

Essays in Biochemistry

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Published in final edited form as:Trepte, P., Strempel, N., Wanker, E.E. Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures. Abstract:Polyglutamine ( This chapter reviews the current literature regarding misfolding and aggregation of polyQ-containing disease proteins. We specifically focus on studies that have investigated the amyloidogenesis of polyQ-containing huntingtin exon 1 (HTTex1) fragments. These protein fragments are disease-relevant and play a critical role in HD pathogenesis. We will outline potential mechanisms behind mutant HTTex1 aggregation and toxicity, as well as proteins and small molecules that can modify HTTex1 amyloidogenesis in vitro and in vivo. The potential implications of such studies for the development of novel therapeutic strategies are discussed.

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“…In 2006, Ehrnhoefer et al [80] found that EGCG directly inhibits the aggregation of the huntingtin protein [80]. Since then, it has been shown that EGCG binds directly to a large number of proteins that are involved in protein misfolding diseases and that EGCG inhibits their fibrillization.…”

Section: Mechanism Of Egcg Interventionmentioning

confidence: 99%

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

Bieschke

2013

Neurotherapeutics

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Protein misfolding disorders, such as Alzheimer's disease and Parkinson's disease, have in common that a protein accumulates in an insoluble form in the affected tissue. The process of aggregation follows a mechanism of seeded polymerization. Although the toxic species is still not well defined, the process, rather than the end product, of fibril formation is likely the main culprit in amyloid toxicity. These findings suggest that therapeutic strategies directed against the protein misfolding cascade should focus on depleting aggregation intermediates rather than on large fibrillar aggregates. Recent studies involving natural compounds have suggested new intervention strategies. The polyphenol epi-gallocatechine-3-gallate (EGCG), the main polyphenol in Camilla sinensis, binds directly to a large number of proteins that are involved in protein misfolding diseases and inhibits their fibrillization. Instead, it promotes the formation of stable, spherical aggregates. These spherical aggregates are not cytotoxic, have a lower β-sheet content than fibrils, and do not catalyze fibril formation. Correspondingly, epi-gallocatechine-3-gallate remodels amyloid fibrils into aggregates with the same properties. Derivatives of Orcein, which is a phenoxazine dye that can be isolated from the lichen Roccella tinctoria, form a second promising class of natural compounds. They accelerate fibril formation of the Alzheimer's disease-related amyloid-beta peptide. At the same time these compounds deplete oligomeric and protofibrillar forms of the peptide. These compounds may serve as proof-of-principle for the strategies of promoting and redirecting fibril formation. Both may emerge as two promising new therapeutic approaches to intervening into protein misfolding processes.

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

Cited by 354 publications

References 31 publications

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Opposite Structural Effects of Epigallocatechin-3-gallate and Dopamine Binding to α-Synuclein

Spontaneous self-assembly of pathogenic huntingtin exon 1 protein into amyloid structures

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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