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.

Keywords: Alzheimer; Huntington; N-acetyl-cysteine; Parkinson; RNS; ROS; RSS; cysteine; proteome; redox.

Figure 1

Schematic overview of cysteine redox proteome (cysteinet) in neurodegenerative diseases. An essential subset of the principal sensitive-cysteine-containing proteins (SCCPs) in Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS) are indicated. The scheme also shows some genes associated with the development of AD, PD, HD, FTD, and ALS (see the main text). Protein misfolding and defective ubiquitin-proteasome function contribute to the pathophysiology and progression of neurodegenerative disorders. A subset of SCCPs concerns the autophagy-lysosome and mitophagy processes leading to the accumulation of proteins and the formation of protein depositions. The impairment of mitochondrial bio-energetic ability, decreased glutathione (GSH) concentrations, and reactive oxygen species (ROS) over-production can also contribute to neuronal death. A mechanism to be investigated is the function of the cysteine redox homeostasis dysregulation working via cysteine switches controlling the process of critical cellular paths.

Figure 2

Mitochondrial SCCPs and cysteinet dysregulation in neurodegenerative disorders. Mitochondria are the primary origin of reactive species, which can redox modulate SCCPs into the organelle participating in its biogenesis, the mitochondrial permeability transition pore (MPTP), mitochondrial import and assembly (Mia) of proteins, and the bio-energetic ability involving enzymes of the tricarboxylic acid cycle (TCAc) and enzymatic complexes of the respiratory electron transport chain and oxidative phosphorylation. The initial insult may affect different SCCPs but would disturb mitochondrial homeostasis and the efficiency of ATP biogenesis. Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), frontotemporal dementia (FTD), and amyotrophic lateral sclerosis (ALS).

Figure 3

Cysteinet deregulation in aging and neurodegenerative disorders. Cysteinet is defined as a bottom-up cellular network integrated by reactive species, the cysteine/cystine and reduced/oxidized glutathione (GSH/GSSG) cycles, and all proteins containing functional cysteines. Sensitive-cysteine-containing proteins (SCCPs) participate in diverse metabolic, signaling, and structural processes but are modulated by the same thiol (-SH) radical. It is hypothesized that cysteine/cysteine ratio disturbance may initiate a domino effect leading in subsequent steps to deregulation of SCCPs including GSH/GSSG status. These SCCPs are redox altered (S-glutathionylation, S-nitrosylation, sulfenylation, disulfide bonds formation), producing reversible or irreversible changes in the protein physiological action, folding and accumulation when proper proteostasis is affected by the cysteinet disturbance. ROS (reactive oxygen species); RNS (reactive nitrogen species); RSS (reactive sulfur species); GSH (reduced glutathione); GSSG (oxidized glutathione). Black and green dots represent oxidized (-S-S-) and reduced (-SH) thiol groups associated with reactive cysteine residues in peptides and proteins.

Figure 4

Potential role of NAC in aging and neurodegenerative disorders. Sensitive-cysteine-containing proteins (SCCPs) can suffer redox modifications of cysteine thiol (-SH) groups (S-glutathionylation, S-nitrosylation, sulfenylation, disulfide bonds formation), culminating in reversible or irreversible modification in the protein role and/or structure, resulting in cysteinet deregulation in age-associated neurodegenerative diseases. These changes can be controlled and repaired by the regular supplementation of NAC, neutralizing the harmful actions of redox changes in multiple SCCPs from diverse pathways. ROS (reactive oxygen species); RNS (reactive nitrogen species); RSS (reactive sulfur species); GSH (reduced glutathione); GSSG (oxidized glutathione); NAC (N-acetyl-cysteine).