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

Abstract

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.

Characterization of the p.L145F and p.S135N Mutations in SOD1: Impact on the Metabolism of Fibroblasts Derived from Amyotrophic Lateral Sclerosis Patients

“…Our results are consistent with previous studies which show imbalanced GSH homeostasis in several models of ALS [72]. Interestingly, lack of GSH or, more generally, of cysteines redox balance, could play a role in the pathogenesis of neurodegenerative diseases [73].…”

Metabolic and Cellular Compartments of Acetyl-CoA in the Healthy and Diseased Brain

“…In the aging brain, an increased susceptibility of PDHC, NADP-isocitrate dehydrogenase (IDH-NADP), aconitase and glyceraldehyde-3-phosphate dehydrogenase to Zn and oxidative stress is linked with the presence of numerous cysteine–SH groups in their active centres, which require cytoprotective concentrations of glutathione, lipoamide and other free radical scavengers [ 14 , 106 , 107 ]. The synthesis of these species in aged brain decreases, whereas production of free radicals increases.…”

“…As a result, several key enzymes of acetyl-CoA and energy metabolism are oxidatively modified [ 107 ]. This may be one of the causes of the increased incidence of Alzheimer’s disease and other neurodegenerative conditions in aged populations [ 106 , 108 ]. It would justify supplementation of those patients with N-acetyl-cysteine, tocopherol, glutathione or lipoamide as an adjuvant therapy [ 106 , 108 , 109 ].…”

Research Status and Prospect of Non-Viral Vectors Based on siRNA: A Review

“…Gene therapy is a promising therapeutic strategy [ 2 ], which can be operated at the gene level to address the occurrence of diseases fundamentally [ 3 ] and provide more possibilities and flexibility than drug therapy [ 4 ]. Gene therapy will make great achievements in areas where there is no treatment or poor efficacy at present [ 5 ], especially in neurodegenerative diseases [ 6 , 7 ], congenital genetic diseases [ 8 , 9 ], and malignant tumors [ 10 , 11 ]. Among the reported methods for gene delivery, RNA interference (RNAi) has been studied and developed extensively [ 6 ].…”

“…Gene therapy will make great achievements in areas where there is no treatment or poor efficacy at present [ 5 ], especially in neurodegenerative diseases [ 6 , 7 ], congenital genetic diseases [ 8 , 9 ], and malignant tumors [ 10 , 11 ]. Among the reported methods for gene delivery, RNA interference (RNAi) has been studied and developed extensively [ 6 ]. RNAi refers to the phenomenon that small double-stranded RNA can specifically degrade or inhibit the expression of homologous mRNA, thus inhibiting or shutting down the expression of specific genes [ 12 , 13 , 14 , 15 ].…”