A synergistic small-molecule combination directly eradicates diverse prion strain structures

Roberts, Blake E; Duennwald, Martin L.; Wang, Huan; Chung, CH; Lopreiato, Nicholas P; Sweeny, Elizabeth A.; Knight, Martha; Shorter, James

doi:10.1038/nchembio.246

Cited by 94 publications

(248 citation statements)

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“…3), further indicated that EGCG directly bound and stabilised TTR tetramer in vitro, and induced TTR oligomerisation in cells 34 . The pharmaceutical mechanism of EGCG curing of yeast prions [PSI] could be via stabilisation of the native prion domain Sup35 as well 35 .…”

Section: Attenuation Of Tdp-43 Degradation By Egcgmentioning

confidence: 99%

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

et al. 2012

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Section: Attenuation Of Tdp-43 Degradation By Egcgmentioning

confidence: 99%

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

et al. 2012

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“…Alzheimer | Parkinson | catechine | misfolding | oligomer P revious studies have shown that the polyphenol (-)-epi-gallocatechine gallate (EGCG), found in large amounts in green tea, has antiamyloidogenic properties and modulates the misfolding of disease proteins and prions (1)(2)(3)(4)(5). EGCG directly binds to unfolded polypeptide chains and inhibits β-sheet formation, an early event in the amyloid formation cascade (6).…”

mentioning

confidence: 99%

EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

Bieschke

Russ

Friedrich

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

909

926

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Protein misfolding and formation of β-sheet-rich amyloid fibrils or aggregates is related to cellular toxicity and decay in various human disorders including Alzheimer's and Parkinson's disease. Recently, we demonstrated that the polyphenol (-)-epi-gallocatechine gallate (EGCG) inhibits α-synuclein and amyloid-β fibrillogenesis. It associates with natively unfolded polypeptides and promotes the self-assembly of unstructured oligomers of a new type. Whether EGCG disassembles preformed amyloid fibrils, however, remained unclear. Here, we show that EGCG has the ability to convert large, mature α-synuclein and amyloid-β fibrils into smaller, amorphous protein aggregates that are nontoxic to mammalian cells. Mechanistic studies revealed that the compound directly binds to β-sheetrich aggregates and mediates the conformational change without their disassembly into monomers or small diffusible oligomers. These findings suggest that EGCG is a potent remodeling agent of mature amyloid fibrils.Alzheimer | Parkinson | catechine | misfolding | oligomer P revious studies have shown that the polyphenol (-)-epi-gallocatechine gallate (EGCG), found in large amounts in green tea, has antiamyloidogenic properties and modulates the misfolding of disease proteins and prions (1-5). EGCG directly binds to unfolded polypeptide chains and inhibits β-sheet formation, an early event in the amyloid formation cascade (6). In the presence of EGCG, the assembly of a new type of unstructured, SDSstable, nontoxic oligomer was observed, instead of the expected formation of β-sheet-rich aggregates. This suggested that the compound redirects aggregation prone polypeptides into offpathway protein assemblies (6), as has since been confirmed for other flavonoids (7).These findings raise the question of whether EGCG might also be able to disassemble preformed, β-sheet-rich structures as well as earlier intermediates of fibrillogenesis. Other small molecules such as curcumin or short β-sheet breaker peptides were described to have this ability; however, their mechanism of action has not been elucidated (8,9). In the present study, we examined the ability of EGCG to alter the structure of mature amyloid fibrils with biochemical and biophysical as well as cell-based assays. Results and DiscussionTo study the effect of EGCG on preformed amyloid aggregates, we first produced α-synuclein (αS) fibrils by incubating natively unfolded monomers (100 μM) at 37°C for 7 d in phosphate buffer. Then aggregates were characterized by EM, atomic force microscopy (AFM), Thioflavin T (ThT) binding assays, and CD spectroscopy (Fig. S1). We observed that the in vitro generated αS aggregates have a β-sheet structure and a fibrillar morphology. Moreover, they efficiently bind the dye ThT, supporting previously published results (10).Next, we added an equimolar concentration of EGCG to the fibrils (50 μM αS monomer equivalent). The effect of the compound was monitored by time-resolved EM and AFM. We found that EGCG very efficiently remodels the ordered, fibrillar morphology ...

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“…The general mechanism of EGCG has now been confirmed in various misfolded protein systems [81,95,96] and the yeast prion Sup35 [86]. However, mechanistic details seem to depend on the stability of the protein aggregates that are formed with the aid of EGCG.…”

Section: Mechanism Of Egcg Interventionmentioning

confidence: 96%

“…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. Examples include αS [81,82], Aβ [36,82], transthyretin [83], lysozyme [84], the prion protein PrP [85], and the yeast prion Sup35 [86].…”

Section: Mechanism Of Egcg Interventionmentioning

confidence: 99%

“…Disassembly or transformation of fibrils by EGCG has also been observed for several other amyloid-forming proteins. After treatment with EGCG, the yeast prion Sup35 loses its ability to replicate the fibrillar structure [86]. EGCG degrades fibrils of transthyretin [96]; fibrils of merozoite surface protein 2 are also transformed into an amorphous structure by EGCG [103].…”

Section: Disassembly and Remodeling Of Amyloid Depositsmentioning

confidence: 99%

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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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A synergistic small-molecule combination directly eradicates diverse prion strain structures

Cited by 94 publications

References 50 publications

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

The self-interaction of native TDP-43 C terminus inhibits its degradation and contributes to early proteinopathies

EGCG remodels mature α-synuclein and amyloid-β fibrils and reduces cellular toxicity

Natural Compounds May Open New Routes to Treatment of Amyloid Diseases

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