Cysteine inhibits the fibrillisation and cytotoxicity of amyloid-β 40 and 42: implications for the contribution of the thiophilic interaction

Takai, Eisuke; Uda, Ken; Yoshida, Teruo; Zako, Tamotsu; Maeda, Mizuo; Shiraki, Kentaro

doi:10.1039/c3cp54245a

Cited by 10 publications

(11 citation statements)

References 78 publications

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“…Cysteine impedes the aggregation of Aβ1-40 and Aβ1-42 and the accumulation of amyloidogenic peptides, and it is less cytotoxic than catechin, the most precise blocker of amyloid fibril accumulation [ 384 ]. Moreover, the beneficial impact of NAC was confirmed in a mouse HD model [ 305 ].…”

Section: Modulation Of Cysteinet By N -Acetyl-cyst...mentioning

confidence: 99%

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Martínez-Banaclocha

2022

Antioxidants

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In the last twenty years, significant progress in understanding the pathophysiology of age-associated neurodegenerative diseases has been made. However, the prevention and treatment of these diseases remain without clinically significant therapeutic advancement. While we still hope for some potential genetic therapeutic approaches, the current reality is far from substantial progress. With this state of the issue, emphasis should be placed on early diagnosis and prompt intervention in patients with increased risk of neurodegenerative diseases to slow down their progression, poor prognosis, and decreasing quality of life. Accordingly, it is urgent to implement interventions addressing the psychosocial and biochemical disturbances we know are central in managing the evolution of these disorders. Genomic and proteomic studies have shown the high molecular intricacy in neurodegenerative diseases, involving a broad spectrum of cellular pathways underlying disease progression. Recent investigations indicate that the dysregulation of the sensitive-cysteine proteome may be a concurrent pathogenic mechanism contributing to the pathophysiology of major neurodegenerative diseases, opening new therapeutic opportunities. Considering the incidence and prevalence of these disorders and their already significant burden in Western societies, they will become a real pandemic in the following decades. Therefore, we propose large-scale investigations, in selected groups of people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment, to evaluate supplementation of the diet with low doses of N-acetyl-cysteine, a promising and well-tolerated therapeutic agent suitable for long-term use.

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Section: Modulation Of Cysteinet By N -Acetyl-cyst...mentioning

confidence: 99%

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Martínez-Banaclocha

2022

Antioxidants

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“…Patulin has been shown to induce intra- and intermolecular protein crosslinks in vitro of other amino acids such as lysine, histidine side chains, and alpha-amino groups [ 155 ]. These three amino acids (cysteine, lysine, histidine) are found in Aβ [ 156 , 157 , 158 , 159 , 160 ] with effects of patulin on these amino acids that possibly are responsible for Aβ electrostatic nature and promotion of Aβ oligomer formation.…”

Section: Patulin and Lps Effect Electrostatic Aβ Oligomer Formatiomentioning

confidence: 99%

Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

Martins

2015

IJMS

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Chronic neurodegenerative diseases are now associated with obesity and diabetes and linked to the developing and developed world. Interests in healthy diets have escalated that may prevent neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease. The global metabolic syndrome involves lipoprotein abnormalities and insulin resistance and is the major disorder for induction of neurological disease. The effects of bacterial lipopolysaccharides (LPS) on dyslipidemia and NAFLD indicate that the clearance and metabolism of fungal mycotoxins are linked to hypercholesterolemia and amyloid beta oligomers. LPS and mycotoxins are associated with membrane lipid disturbances with effects on cholesterol interacting proteins, lipoprotein metabolism, and membrane apo E/amyloid beta interactions relevant to hypercholesterolemia with close connections to neurological diseases. The influence of diet on mycotoxin metabolism has accelerated with the close association between mycotoxin contamination from agricultural products such as apple juice, grains, alcohol, and coffee. Cholesterol efflux in lipoproteins and membrane cholesterol are determined by LPS with involvement of mycotoxin on amyloid beta metabolism. Nutritional interventions such as diets low in fat/carbohydrate/cholesterol have become of interest with relevance to low absorption of lipophilic LPS and mycotoxin into lipoproteins with rapid metabolism of mycotoxin to the liver with the prevention of neurodegeneration.

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“…Intense efforts have been directed towards identifying or designing compounds that are able to counteract fibrillogenesis through: i) the stabilization of the native state, ii) the sequestration of monomeric peptide, iii) the stabilization or promotion of off-pathway oligomers, iv) the breakage of the β-sheet terminating the fibril elongation, or v) fibril disassembly 20 . Ruthenium complexes 21 , cysteine 22 or 2,5-diarylated thiophenes 23 have recently been found to disassemble amyloid fibrils and/or to inhibit their formation. In addition, natural polyphenolic compounds are considered as promising pharmaceuticals against amyloid diseases 10 .…”

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confidence: 99%

Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis

Marino

Pauwels

Casasnovas

et al. 2015

Sci Rep

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Protein aggregation with the concomitant formation of amyloid fibrils is related to several neurodegenerative diseases, but also to non-neuropathic amyloidogenic diseases and non-neurophatic systemic amyloidosis. Lysozyme is the protein involved in the latter, and it is widely used as a model system to study the mechanisms underlying fibril formation and its inhibition. Several phenolic compounds have been reported as inhibitors of fibril formation. However, the anti-aggregating capacity of other heteroaromatic compounds has not been studied in any depth. We have screened the capacity of eleven different hydroxypyridines to affect the acid-induced fibrillization of hen lysozyme. Although most of the tested hydroxypyridines alter the fibrillation kinetics of HEWL, only 3-hydroxy-2-methylpyridine, 3-hydroxy-6-methylpyridine and 3-hydroxy-2,6-dimethylpyridine completely abolish fibril formation. Different biophysical techniques and several theoretical approaches are combined to elucidate their mechanism of action. O-methylated 3-hydroxypyridines bind non-cooperatively to two distinct but amyloidogenic regions of monomeric lysozyme. This stabilises the protein structure, as evidenced by enhanced thermal stability, and results in the inhibition of the conformational transition that precedes fibril assembly. Our results point to o-methylated 3-hydroxypyridines as a promising molecular scaffold for the future development of novel fibrillization inhibitors.

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Cysteine inhibits the fibrillisation and cytotoxicity of amyloid-β 40 and 42: implications for the contribution of the thiophilic interaction

Cited by 10 publications

References 78 publications

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases

Overnutrition Determines LPS Regulation of Mycotoxin Induced Neurotoxicity in Neurodegenerative Diseases

Ortho-methylated 3-hydroxypyridines hinder hen egg-white lysozyme fibrillogenesis

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