How Epigallocatechin‐3‐gallate and Tetracycline Interact with the Josephin Domain of Ataxin‐3 and Alter Its Aggregation Mode

Bonanomi, Marcella; Visentin, Cristina; Natalello, Antonino; Spinelli, Michela; Vanoni, Marco; Airoldi, Cristina; Regonesi, Maria Elena; Tortora, Paolo

doi:10.1002/chem.201503086

Cited by 19 publications

(19 citation statements)

References 62 publications

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“…This data supports the hypothesis of a supramolecular interaction between p17 and tetracycline—similar to that observed between tetracycline and other amyloidogenic proteins 47 , 48 — and indicates that this drug may trigger the formation of new, non-toxic protein assemblies. Saturation transfer difference (STD)-NMR spectroscopy 47 , 48 was applied to characterise the molecular recognition events involving p17 and tetracycline. The 1 H-NMR spectra showed a decrease in the signal intensities over time, particularly for protein signals (Supplementary Figs S14 and S16 ).…”

Section: Resultssupporting

confidence: 86%

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HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders

Zeinolabediny

Caccuri

Colombo

et al. 2017

Sci Rep

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Human immunodeficiency virus type-1 (HIV-1)-associated neurocognitive disorder (HAND) remains an important neurological manifestation that adversely affects a patient’s quality of life. HIV-1 matrix protein p17 (p17) has been detected in autoptic brain tissue of HAND individuals who presented early with severe AIDS encephalopathy. We hypothesised that the ability of p17 to misfold may result in the generation of toxic assemblies in the brain and may be relevant for HAND pathogenesis. A multidisciplinary integrated approach has been applied to determine the ability of p17 to form soluble amyloidogenic assemblies in vitro. To provide new information into the potential pathogenic role of soluble p17 species in HAND, their toxicological capability was evaluated in vivo. In C. elegans, capable of recognising toxic assemblies of amyloidogenic proteins, p17 induces a specific toxic effect which can be counteracted by tetracyclines, drugs able to hinder the formation of large oligomers and consequently amyloid fibrils. The intrahippocampal injection of p17 in mice reduces their cognitive function and induces behavioral deficiencies. These findings offer a new way of thinking about the possible cause of neurodegeneration in HIV-1-seropositive patients, which engages the ability of p17 to form soluble toxic assemblies.

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Section: Resultssupporting

confidence: 86%

“…elegans . Due to the multiple mechanisms of action 45 , this drug exerts beneficial in vitro and in vivo effects against a variety of amyloidogenic proteins 45 , 48 , 49 , 65 , 66 . Significant hints have come from a study recently performed on patients affected by Creutzfeldt-Jakob disease.…”

Section: Discussionmentioning

confidence: 99%

HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders

Zeinolabediny

Caccuri

Colombo

et al. 2017

Sci Rep

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“…S-11). In conclusion, these and previously published results point to EGCG as a generic binder [34][35][36][37][38][39][40][41][42] and modulator 41,42 of protein structure.…”

Section: Egcg Binding Promotes As Compactionsupporting

confidence: 79%

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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“…Epigallocatechin is believed to inhibit the formation of the amyloidgenic β-sheet-rich structures that are known components in protein aggregation, and steer formation towards non-toxic forms. While tetracycline did not appear to create any structural alterations, it significantly increased the solubility of the previously insoluble aggregates [231].…”

Section: Prevention Of Misfolding and Protein Aggregationmentioning

confidence: 79%

“…However, this is by no means a robust therapy and further studies would need to be conducted on the effects of upregulation and the effectiveness of calcium pantothenate to modulate HSPB expression to levels required for therapeutic benefit. Other drugs such as epigallocatechin and tetracycline have been linked to altered aggregation in SCA diseases, most notably SCA3 [231,232]. The two drugs have been shown to positively alter aggregation and toxicity of mutant ataxin-3 via two distinct mechanisms.…”

Section: Prevention Of Misfolding and Protein Aggregationmentioning

confidence: 99%

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

McIntosh¹,

Htut²,

Fletcher³

et al. 2017

J Genet Syndr Gene Ther

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Spinocerebellar ataxias are a large group of heterogeneous diseases that all involve selective neuronal degeneration and accompanied cerebellar ataxia. These diseases can be further broken down into discrete groups according to their underlying molecular genetic cause. The most common are the polyglutamine ataxias, of which there are six; Spinocerebellar ataxia type 1, 2, 3, 6, 7 and 17. These diseases are characterised by a pathological expanded cytosine-adenine-guanine (CAG) repeat sequence, in the protein coding region of a given gene. Common clinical features include lack of coordination and gait ataxia, speech and swallowing difficulties, as well as impaired hand and motor functions. The polyglutamine spinocerebellar ataxias are typically late onset diseases that are progressive in nature and often lead to premature death, for which there is currently no known cure or effective treatment strategy. Although caused by the same molecular mechanism, the causative gene and associated protein differ for each disease. The exact mechanism by which disease pathogenesis is caused remains elusive. However, the variable (CAG) n repeats are codons that may be translated to an expanded glutamine tract, leading to conformational changes in the protein, giving it a toxic gain of function. Several pathogenic pathways have been implicated in polyglutamine spinocerebellar ataxia diseases, such as the hallmark feature of neuronal nuclear inclusions, protein misfolding and aggregation, as well as transcriptional dysregulation. These pathways are attractive avenues for potential therapeutic interventions, as the potential to treat more than one disease exists. Research is ongoing, and several promising therapies are currently underway in an attempt to provide relief for this devastating class of diseases.. However, mutations can arise de novo, through errors in DNA replication such that two genetically healthy parents can give rise to an affected child.There are currently six characterised polyQ SCAs (1, 2, 3, 6, 7 and 17) (Table 1), and together with three other diseases, namely Huntington's disease, spinal and bulbar muscular atrophy and dentatorubropallidoluysian atrophy (DRPLA), form a larger category of polyQ diseases [7][8][9][10]. Th ere is little relief for individuals suffering from polyQ SCA disorders, with symptomatic treatments the only available option. Long term pharmacological treatment, although admirable, tends to fall short in an effective management strategy, as unwanted complications and low drug efficacy still exist. In addition, none of these diseases have any treatments that slow the progression of the disease; leaving affected individuals with the daunting reality that time may be a severe limiting factor. Several experimental approaches are currently being assessed to overcome these difficulties. This review will focus on the clinical and molecular features of polyQ SCA diseases (which will be referred to as SCA diseases), as well as highlight several promising and emerging therapeutic strategies...

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How Epigallocatechin‐3‐gallate and Tetracycline Interact with the Josephin Domain of Ataxin‐3 and Alter Its Aggregation Mode

Cited by 19 publications

References 62 publications

HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders

HIV-1 matrix protein p17 misfolding forms toxic amyloidogenic assemblies that induce neurocognitive disorders

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

Polyglutamine ataxias: From Clinical and Molecular Features to Current Therapeutic Strategies

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