Inhibiting toxic aggregation of amyloidogenic proteins: A therapeutic strategy for protein misfolding diseases

Cheng, Biao; Gong, Hao; Hongwen, Xiao; Petersen, Robert B.; Zheng, Ling; Huang, Kun

doi:10.1016/j.bbagen.2013.06.029

Cited by 192 publications

(132 citation statements)

References 179 publications

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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%

“…Such inhibitors have attracted attention for the development of new drugs against amyloidoses 2,3 . A promising anti-amyloidogenic compound is the antioxidant molecule epigallocatechin-3-gallate (EGCG), the major green tea polyphenol which displays neuroprotective and anticancerogenic effects in cellular and animal models 4,5 . EGCG redirects AS aggregation into offpathway, non-toxic, SDS-resistant, spherical and nanostructured oligomers of ~20-nm diameter 6 .…”

Section: Introductionmentioning

confidence: 99%

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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%

Section: Introductionmentioning

confidence: 99%

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

et al. 2016

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“…It can be considered that this analytical system is an alternative to the conventional staining method using Congo-red reagent [1]. Furthermore, the fact that the structural changes of the amyloid fibrils after FEL irradiation could be observed using SR-IRM means that this analytical system can be considered as a possible screening assay for inhibitors targeting amyloid fibrils [7]. For example, the inhibitory effect of candidate drugs on the dissociation of amyloid fibrils on the substrate could be tested using SR-IRM as shown in this study.…”

Section: Discussionmentioning

confidence: 99%

“…Amyloid fibrils are recognized as a clinical target, and they have a common secondary structure, cross-β structure, that is formed by peptides and various proteins [3]. Decreasing the amount of amyloid fibrils in tissues is considered to be an effective treatment for amyloidosis, but it is difficult to dissociate the robust fibril structure unless organic solvents or synthetic molecules are used [6] [7].…”

Section: Introductionmentioning

confidence: 99%

Synchrotron-Infrared Microscopy Analysis of Amyloid Fibrils Irradiated by Mid-Infrared Free-Electron Laser

Kawasaki¹,

Yaji²,

Imai³

et al. 2014

AJAC

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Amyloid fibrils are widely recognized as a cause of serious amyloidosis such as Alzheimer's disease. Although dissociation of amyloid fibril aggregates is expected to lead to a decrease in the toxicity of the fibrils in cells, the fibril structure is robust under physiological conditions. We have irradiated amyloid fibrils with a free-electron laser (FEL) tuned to mid-infrared frequencies to induce dissociation of the aggregates into monomer forms. We have previously succeeded in dissociating fibril structures of a short peptide of the thyroid hormone by tuning the oscillation frequency to the amide I band, but the detailed structural changes of the peptide have not yet been determined at a high spatial resolution. Synchrotron-radiation infrared microscopy (SR-IRM) is a powerful tool for in situ analysis of minute structural changes of various materials, and in this study, the feasibility of SR-IRM for analyzing the microscopic conformational changes of amyloid fibrils after FEL irradiation was investigated. Reflection spectra of the amyloid fibril surface showed that the amide I peaks shifted to higher wave numbers after the FEL irradiation, indicating that the initial β-sheet-rich structure transformed into a mixture of non-ordered and turn-like peptide conformations. This result demonstrates that conformational changes of the fibril structure after the FEL irradiation can be observed at a high spatial resolution using SR-IRM analysis and the FEL irradiation system can be useful for dissociation of amyloid aggregates.

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“…Among natural compounds, most Aβ inhibitors present a polyphenolic core [42], including resveratrol [43], myricetin [44], curcumin [45], caffeine [46].…”

Section: Aβ Aggregation Inhibitormentioning

confidence: 99%

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

Pietrobono¹,

Giacomelli²,

Ml³

et al. 2017

Glob Drugs Therap

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Inhibiting toxic aggregation of amyloidogenic proteins: A therapeutic strategy for protein misfolding diseases

Cited by 192 publications

References 179 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

Synchrotron-Infrared Microscopy Analysis of Amyloid Fibrils Irradiated by Mid-Infrared Free-Electron Laser

Inhibitors of protein aggregates as novel drugs in neurodegenerative diseases

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