key: cord-0027547-9tzmghpa
authors: Martinez-Banaclocha, Marcos
title: N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases
date: 2022-02-18
journal: Antioxidants (Basel)
DOI: 10.3390/antiox11020416
sha: 0d6f297e723c04a63e2f73a89191dd0427fd9518
doc_id: 27547
cord_uid: 9tzmghpa

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.

The significant increase in human life expectancy has resulted in an insidious rise in the prevalence of age-associated neurodegenerative diseases, becoming a true pandemic affecting most countries worldwide. It has been estimated that Alzheimer's disease will affect nearly half of the population over 85 years of age by 2050. There is no remedial therapy for neurodegenerative diseases, and only palliative medications address different symptoms of each condition. Therefore, prevention and early diagnosis of these neurodegenerative diseases are crucial to improving patient outcomes. Though the chances of underdiagnosis and misdiagnosis will probably remain high, some diagnostic tools and imaging techniques help us to detect the brain's activity, the extent of the injury, and the early location of deterioration in the CNS. The discovery that most neurodegenerative diseases share homeostasis deregulation of proteins and pathologic accumulation of specific proteins has prompted a search to find strategies to prevent or interfere with the disturbed proteome of each disorder.

Prevalent neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia (FTD) show differences in clinical presentation and evolution with characteristic alterations affecting the aggregation of specific proteins and their deposition in central and peripheral specific neural cells, which seem typical of each disease. Although the impact on brain dysfunction develops according to different rhythms, the diseases each entail protein accumulation, mitochondrial dysfunction, and oxidative damage that finally end in neuronal death.

We have previously proposed that some common neurodegenerative disorders, such as AD and PD, each involve the dysregulation of the sensitive-cysteine proteome [1] [2] [3] [4] [5] . In the present paper, we extend this proposition to other neurodegenerative diseases, suggesting that a disturbance of the redox cysteine proteome mediates all age-associated degenerative diseases. In an effort to reconcile the role played by many different etiopathogenic factors and associated conditions in neurodegenerative disorders and the progressive pathological evolution of these diseases, with or without individual genetic susceptibility, in addition to toxic environmental factors and age-associated oxidative damage, we propose a mechanism of convergent redox proteomic dysregulation that impairs the biochemical pathways involved in each specific disease.

A scientific and rational strategy to solve the growing problem of neurodegenerative diseases requires a long and aggressive international initiative using well-known and safe compounds. N-acetyl-cysteine (NAC) is a natural amino acid, modified to increase its bio-disponibility, that may be easily incorporated into the diet. NAC has proven beneficial effects in diabetes, hypertension, obesity, and cardiovascular disturbance management, many of which are associated with and contribute to neurodegeneration. Since the prevention of neurodegenerative diseases remains without clinically significant therapeutic advancement, the present review proposes a large-scale intervention in people over 40 years of age with decreased blood glutathione levels, comorbidities, and/or mild cognitive impairment involving supplementation of the diet with 600 mg of NAC three times a week. These interventions have the potential to slow the onset and progression of dementia, reducing the neurodegenerative disease burden.

Protein homeostasis (proteostasis) is central to maintaining the functional cellular proteome, a dynamic complex process involving response to different physiological and pathological conditions [6, 7] . Proteostasis comprises synchronization from protein synthesis in the ribosome through to posttranslational modification, trafficking to each subcellular compartment, assembly into protein macro-complexes, signaling, and degradation [7, 8] , depending on proper protein folding and transport by chaperones [9, 10] . The post-translational modification of proteins (PTMPs) increases the complexity and diversity of proteins, which are differentially expressed in distinct tissues determining the versatility and functionality of most biochemical pathways in the cell. PTMPs principally include phosphorylation, acetylation, allosteric modification, and redox regulations. Redox PTMPs affect many different amino acids, but cysteine is the most readily affected, possessing a thiol group (-SH) which is deprotonated at physiological pH, allowing reversible redox modifications.

Redox-regulated proteins comprise the redox proteome (redoxome), in which specific cysteine residues play a crucial role through reversible redox modifications [11, 12] . The number of cysteine residues in proteins comprises approximately 2% of the total, though this amino acid is favorably conserved in proteins through evolution because of its highly functional role. Since cysteine is derived from methionine, it is not considered an essential amino acid. Nevertheless, cysteine is fundamental to maintaining the synthesis, structure, and functional versatility of many proteins and small polypeptides, such as glutathione. Sensitive-cysteine residues in proteins act in diverse redox reactions, including the reversible change of the catalytic function in enzymes, such as in the mitochondrial respiratory chain. Sensitive cysteine residues in proteins also participate in structural and contractile functions supporting the cytoskeletal architecture and movements of cells, the folding and transportation of proteins via membranes, the modulation of cellular signals, the regulation of DNA synthesis and expression, and the retention and consumption of fuels [12, 13] . Quantitative thiol reactivity methods have identified many redox-sensitive cysteine residues in proteins, including proteins involved in translation, histone mod-ification, mRNA splicing, and growth regulatory pathways [12] . These findings have revealed the unexpected importance of the redox cysteine proteome in regulating vital pathways in a complex organism [12] . Notably, 54% of cysteine residues in essential proteins showed similar intrinsic reactivity in C. elegans and human cells. For example, the Cys33 residue in glutathione S-transferase exhibited almost the same reactivity in C. elegans and Homo sapiens [13] . In other cases, such as human glyceraldehyde 3-phosphate dehydrogenase (GAPDH), the reactive Cys158 site within all four orthologs in C. elegans shows the same reactivity in GPD-1 and GPD-2/3 but a higher reactivity in GPD-4, suggesting there is a correlation between the amino acid sequence and intrinsic cysteine reactivity [12] . However, subtle changes in flanking sequences can influence redox cysteine reactivity, and, therefore, the redox sensitivity of cysteine residues is modulated by their microenvironment [12] .

Redox modification of sensitive-cysteine residues maintains the thiol status of critical proteins, defending the cell against reactive species and contributing to the detoxification of xenobiotics and their metabolites. Hence, cysteine is viewed as the main extracellular antioxidant, encountered principally as disulfide cystine because the extracellular conditions are rather oxidizing. This reservoir is integrated and complements the principal intracellular antioxidant glutathione (GSH), though the two are not in balance [14] . The cysteine residues of the tripeptide GSH participate in most of the complex network of enzyme-catalyzed reactions in practically all sub-cellular organelles and the cell's cytoplasm [14] . Glutathione can reduce disulfide bridges in cytoplasmic proteins, when it is converted to glutathione disulfide (GSSG) that is reduced back through glutathione reductase utilizing NADPH as an electron donor. In addition, GSH is a cofactor for diverse antioxidant enzymes, such as glutathione reductases, glutathione peroxidases, and glutathione S-transferases, which participate in redox homeostasis [14] .

The broad but specific distribution of redox-sensitive cysteines across the proteome indicates that essential physiological functions must be subject to exquisite redox regulation, highlighting the biological importance of redox-sensitive cysteine residues in vivo. The metabolism produces reactive oxygen, nitrogen, and sulfur species (ROS, RNS, and RSS, respectively) that operate as cellular redox homeostasis intermediates, regulating different metabolic processes through reversible or irreversible redox modifications of reactive cysteine residues [1, 11, 12, 15] . Reactive species trigger radical transfer, a defensive cellular instrument against oxidative injury in proteins, in which oxidation at specific sites in the protein involves a chain of electron transfer towards further redox amino acid residues, such as cysteine or methionine, to neutralize the oxidative impairment at the initial point [16] . This mechanism works physiologically at the catalytic sites of some enzymes and among diverse enzymatic proteins, such as in the mitochondrial respiratory chain [17] .

The proteasome is liable for the ubiquitin-dependent and -independent degradation of oxidatively damaged proteins. Under physiological conditions, most misfolded proteins are ubiquitylated and degraded [18] . Protein degradation in the proteasome requires unfolded and readily available domains in those proteins susceptible to degradation, which depends on successive substrate processing through to final degradation [18, 19] . The initial binding of the ubiquitinated protein to the E1 ubiquitin-activating enzyme depends on a thiol ester bond [20] , as is the case for transferring the activated ubiquitin to the E2 ubiquitin-conjugating enzyme via an active cysteine residue within the E2 protein [20, 21] . Furthermore, ubiquitin E3 ligases contain reactive cysteine residues that modulate ubiquitylation and suffer cysteine modifications affecting the ligase activity. Indeed, the redox-regulated E3 ligase adaptor Kelch-like ECH-associated protein 1 (Keap1) has numerous reactive cysteines determining its interactions with the redox-associated transcription factor Nrf2 [22, 23] . Nrf2 is a critical component of the antioxidant cell response by incorporating signals derived from misfolded protein accumulation to coordinate an adequate transcriptional response. In consequence, Nrf2 coordinates the endoplasmic reticulum (ER), the proteasome, and autophagy functionality [24, 25] , participating in the cellular response against oxidative and electrophilic compounds. In this regard, the ubiqui-tin E3 ligase Keap1 acts as a reactive cysteine redox sensor leading to Nrf2 ubiquitination and proteasomal degradation.

Moreover, Nrf2 regulates vital enzymes of the GSH metabolism in the brain, such as cystine/glutamate transport, γ-glutamate-cysteine synthetase (γ-GS), glutamate-cysteine ligase, glutathione reductase (GR), and glutathione peroxidase (GPX) [25] . Oxidative protein folding in the ER depends on the protein disulfide isomerase (PDI) and the endoplasmic oxidoreductin 1 (Ero1) sulfhydryl oxidases as disulfide donors. PDI modulates protein folding, catalyzing disulfide bonds between reactive cysteine residues due to the redox reactions of its cysteine residues. Interestingly, the oxidative modification of a single cysteine residue (Cys663) within the kinase activation loop of the ER protein, IRE-110, can suppress the unfolded protein response stimulating the p38 mitogen-activated protein kinase (MAPK) antioxidant signal simultaneously [24] .

The redox cysteine proteome in C. elegans is expressed through different tissues and organs with sensitive-cysteine proteins widely distributed in the primary cellular organelles, including mitochondria, the endoplasmic reticulum, and the nucleus [12] . Genetic and molecular analyses of the C. elegans redoxome have identified many fundamental cellular processes, including the ubiquitin-proteasome pathway that showed a high representation of functional cysteine proteins. The authors suggested that the cysteine enrichment in critical metabolic processes (i.e., glycolysis, the tricarboxylic acid cycle, and the pentose phosphate pathway) is consistent with the hypothesis that the redox modification of proteins modulates metabolic fluxes to maintain cellular redox homeostasis [12] . Thus, redox regulation of sensitive-cysteines may control the ubiquitylation and the subsequent proteasomal degradation of proteins, serving as a mechanism for reactive species to sense and back-regulate practically all the metabolism [7, 26] . This proteasomal cysteine redox sensitivity plays a critical role in cellular redox homeostasis, and it appears to be central to understanding neurodegeneration.

The cellular redox proteome encompasses all proteins that suffer reversible and irreversible redox reactions under physiological and pathological conditions. Cys, Met, and seleno-cysteine residues at the shell and other steric functional sites of proteins are especially susceptible to redox changes. Nevertheless, other amino acids (Trp, Tyr, and Arg) can react with derivatives from oxidative metabolism [1, 15] . Therefore, the sensitive-cysteine redox proteome (cysteinet) is considered one of the functional compartments of the redox proteome. Cysteinet engages all peptides and proteins that possess functional redox cysteine residues in their structure, including the small tripeptide glutathione. This network interconnects reactive species (e.g., ROS, RNS, and RSS) with cysteine-containing proteins to control cellular survival, regeneration, and death [1] . These sensitive-cysteine-containing proteins (SCCPs) are regulated by the same thiol radical into cysteine residues, though they can have diverse metabolic, signaling, and structural functions. SCCPs function as cellular detectors, synchronizing over brief timescales distinct cellular functions under the maintenance of the redox environment. Sensitive-cysteines can suffer various redox changes (e.g., s-glutathionylation, s-nitrosylation, sulfenylation, disulfide bond formation) under particular physiological or pathological conditions, resulting in a reversible shift in protein function [1] . It has been suggested that cysteinet is crucial in neurodegeneration [1] [2] [3] [4] [5] and brain development, which is also under the control of SCCPs at very early stages [27] . Further investigations may be necessary to better understand psychiatric diseases, such as schizophrenia and bipolar disorders [28, 29] .

Aging is associated with the oxidative damage of macromolecules mediated by reactive species [30] [31] [32] . Aged healthy humans show an age-associated decline in the cysteine/cystine proportion throughout life, and reduction in the total glutathione content and GSH/GSSG ratio [33] , indicating an age-related modification of redox homeostasis toward pro-oxidant states [34] , affecting multiple regulatory paths that depend on the integrity of SCCPs [35, 36] , including mitochondrial ones [37] . Thus, aging raises the rate of irreversible injury to structural and metabolic proteins hampering normal cellular functions and homeostasis [1] . Proteomic studies show that aging is associated with a deleterious transition in redox-regulated proteins resulting in substantial shifts in the glycolytic enzymes and the regulatory enzymes handling energy metabolism in muscular post-mitotic cells [38] . Moreover, normal brain aging is characterized by deregulated expression of specific aggregation-prone proteins predisposing to Aβ and tau deposition, as well as suboptimal expression of homeostatic proteins [39] . Genome-wide gene expression investigations have supplied confirmation of decreased mitochondrial function during aging and declined gene expression implicated in mitochondrial energy metabolism in humans with cognitive deterioration and AD [40] . On the other hand, the effect of caloric restriction in aging is mediated by decrease in body temperature, the rate of metabolism, and decreased generation of reactive species balancing age-related oxidative injury and stabilizing mitochondrial activity in neurons [41] . Consequently, age-associated oxidative change of SCCPs may be the Achilles' heel for senescence and neurodegenerative disturbances [1] .

Recent studies demonstrate that cysteine reactivity profiling can complement transcriptomic and proteomic analyses in complex organisms through activity-based protein profiling. This technique identifies reactive cysteine residues in catalytic critical sites in complex proteomes [42] . Protein homeostasis is one of the essential mechanisms of cells maintaining the adequate functional proteome in each organelle and its integration in different stress-inducing conditions, including cellular aging, which is associated with a decline in proteostasis [6, 7] . Proteostasis is a high-energy-dependent part of the proteome that involves different functions, such as editing, transfer, folding, and degradation of proteins across cellular organelles, including the cytosol, nucleus, mitochondria, and endoplasmic reticulum (ER) [6, 7, 26] . Proteins are actively synthesized in the ER, and cysteine residues supply the proper disulfide bonds to provide the 3D structure and conformational stability to the recently synthesized proteins [43] . Then, the redox environment of the ER ensures the correct folding of proteins that is exquisitely regulated by a network of oxidases and PDIs [6, 7, 26] . It has been shown that the redox states in the cytosol and the ER are expressed differently in aging, stress-inducing circumstances and diseases. The ER becomes more reduced while the cytosol becomes more oxidizing in reaction to these stress-inducing conditions [6, 7, 26] .

The relationship between redox cysteine modifications and aging involves proteins from several pathways to maintain protein homeostasis and cell survival. Wide-scale proteomic approaches demonstrated the presence of cysteine redox networks with tissuespecific changes in thiol oxidation during aging, including tRNA multi-synthetase complex members [6, 7] . Therefore, thiol reduction during aging suggests that redox versatility is compromised [6, 7] , likely contributing to age-related neurodegeneration [1] .

The following sections review the critical role of the disturbance of sensitive-cysteine thiol groups in SCCPs from different cellular pathways and their integration in the proposed cysteinet deregulation contributing to proteostasis impairment in neurodegeneration (Figures 1-3) .

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. 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.

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).

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, 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). 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, 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-cysteinecontaining 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.

Age-associated disorders, including neurodegenerative diseases, are accompanied by deregulation in redox protein homeostasis, mitochondrial dysfunction, macromolecular oxidative damage, and accumulation of misfolded proteins into different cellular compartments [1, 6, 7] . Site-specific thiol groups in reactive cysteine residues in proteins serve as redox sensors, and this sensitivity makes them work as switches to synchronize diverse biochemical pathway functions. This interactive type of post-translational modification by small molecules (ROS, RNS, and RSS) leads to the close regulation of thousands of proteins in the cytosol and specific organelle compartments in cells [1, 6, 7, [11] [12] [13] . Redoxregulated proteins can suffer different types of reversible (palmitoylation, sulfenic acid) or irreversible (prenylation, sulfinic, and sulfonic acid) redox modifications in response to various small oxidants and compartmentalized subcellular pH [6, 7, 44] . Indeed, the cellular antioxidant machinery (thioredoxins, glutaredoxins, peroxiredoxins) uses reversible changes in the redox state of its catalytic cysteine residues to restore the redox status of different cellular proteins [44, 45] . Therefore, cysteine redox-modifications of proteins are exquisitely regulated, participating in proper protein folding, function, and secretion through palmitoylation, prenylation, S-nitrosylation, and S-glutathionylation [44, 45] .

It has been demonstrated that the expression of amyloid fibrils induces a shift toward cytosolic oxidizing conditions in neuronal cells and vice versa, suggesting the existence of a complex signaling mechanism for redox state regulation [46] , which we have proposed to be organized into a broad cellular and intercellular sensitive-cysteine network called cysteinet [1] . It remains to be clarified how cysteinet is regulated and deregulated in pathological conditions, including aging and neurodegenerative diseases. Small oxidizing and reducing molecules, such as hydrogen peroxide, nitric oxide, hydrogen sulfide, NADP/NADPH, free cysteine/cystine, and GSH/GSSG mediate this organism-broad redox network. The impairment of proteostasis in some cells could affect neighboring cells' protein folding conditions, leading to redox homeostasis imbalances affecting protein transport between cells, disturbing the redox response in distinct compartments and tissues [1, 46] .

AD is the most frequent age-associated neurodegenerative disorder characterized by aberrant processing of the amyloid precursor protein (APP), increasing Aβ1-42 peptide accumulation, and formation of intraneuronal neurofibrillary tangles by the hyperphosphorylation of the microtubule-associated protein tau (MAPT) in the brain [47] [48] [49] [50] [51] . The accumulation of both proteins has been associated with neuronal loss and cognitive impairment in AD patients [52, 53] . To integrate proteostasis impairment in AD, we have proposed that genetic, mitochondrial, toxic, metabolic, inflammatory, and age-related factors can converge in the deregulation of cysteinet that finally results in neuronal degeneration. Therefore, redox protection of SCCPs may contribute to stabilizing proteins against irreversible oxidative damage or revert them to their physiological state [54] . The reversibility of thiol changes permits cysteine residues in proteins to function as regulators in numerous regulatory routes and various structural sites in the cell. Nonetheless, the irreversibility of thiol oxidation causes cumulative deterioration of proteins with harmful effects [55, 56] .

Cysteinet works as a bottom-up biochemical network, formed by reactive species serving as modulators, the cysteine/cystine and GSH/GSSG cycles, and all peptides and proteins with functional cysteine residues in their structure [1] [2] [3] . Cysteine residues in SCCPs may act as cellular sensors engaging, at very short timescale, very different cellular functions [1] [2] [3] [4] [5] .

Diverse etiologic events can contribute to deregulating the age-associated cellular redox balance developing into cysteinet disturbance in age-related neurodegenerative diseases ( Figure 3 ). ROS overproduction has been related to age-associated mitochondrial DNA injury and impairment in bioenergetic capability in patients that are homozygous for apolipoprotein E4, resulting in a dysfunction of cysteinet that can hamper diverse pathways, promoting, among others, Aβ amyloid and tau accumulation (Figures 1-3 ).

ApoE isoforms show arginine to cysteine differences in their N-terminal domains. ApoE4 contains two arginine residues at positions 112 and 158. However, ApoE3 contains a cysteine residue at position 112, while ApoE2 contains two cysteine residues at positions 112 and 158, respectively [57, 58] . These amino acid substitutions in E apolipoproteins result in 3D structural changes with functional consequences [58] . Sensitive-cysteine residues in ApoE2 and ApoE3 may bind and detoxify the free radical 4-hydroxynonenal, a cytotoxic lipid peroxidation by-product. However, ApoE4 homozygosity may contribute to brain aging by its inherent decreased neuroprotective ability because of the absence of reactive cysteine residues in ApoE4 [59] . Therefore, it seems that ApoE isoforms have different redox capacities through sensitive-cysteine residues. ApoE2 and Apo E3 can bind to neuronal nitric oxide synthase (NOS1), and they can be S-nitrosylated in the human hippocampus, potentially regulating lipid metabolism in AD [60] .

The apolipoprotein genotype E4 is the most notable genetic linkage to late-onset AD [61] , and people with the E4 allele have a decreased lifespan [62] and increased chance of suffering from AD [63] . Aβ clearance drops from ApoE2 to ApoE3 to ApoE4, suggesting a connection between the clearance of Aβ and ApoE isoforms [64] . Cys112 in ApoE3 allows the formation of disulfide bridges between ApoE3 molecules forming monomers and homodimers [65] , whereas Cys112 and Cys158 in ApoE2 enable the formation of monomers and homodimers, as well as homopolymers [65] (Figure 1 ). However, the absence of cysteine residues in ApoE4 does not permit the formation of disulfide bonds between ApoE4 molecules and potentially contributes to its decreased efficiency at clearing Aβ. The resulting Aβ accumulation can increase oxidative damage facilitating the onset of AD in APOE4 genotypes. Additionally, the high-temperature requirement protein A1 (HtrA1) is involved in the degradation of APOE4, Aβ, and hyperphosphorylated tau through redoxregulated mechanisms that involve sensitive-cysteine residues in the N-terminal third of the HtrA1 protein, resulting in a 3D structural modification that decreases its binding to APOE4, and possibly to Aβ and tau proteins [66] .

AD brains show increased levels of reactive species affecting critical proteins for neuronal survival and contributing to disease pathophysiology [67] . Mitochondrial dysfunctions occur in AD brains before clinical symptoms and Aβ plaque formation [68] [69] [70] [71] [72] . It seems that synaptic mitochondria are specifically vulnerable in aging and AD [72] [73] [74] , being the primary source of reactive species. Reactive species can significantly modulate SCCPs in the organelle participating in the bio-energetic ability of the cell, including the tricarboxylic acid cycle (TCAc), complexes of the respiratory electron transport chain, and oxidative phosphorylation (Figures 1 and 2 ).

Aconitase and pyruvate dehydrogenase are mitochondrial enzymes redox-regulated by hydrogen peroxide and S-glutathionylation by the oxidation and reduction of specific sensitivecysteine residues [54, 75] . L-carnitine/acyl-carnitine carriers can be S-glutathionylated on Cys136 and Cys155 [75] . In addition, the enzyme succinate dehydrogenase can be Sglutathionylated in oxidizing conditions [75] . Redox modifications by S-glutathionylation are reversible and occur under stress-inducing and physiological conditions. During aging and other stress-inducing conditions with decreased GSH/GSSG balance in the mitochondria, the oxidative shift of these SCCPs may be irreversible.

Mitochondrial complex I of the respiratory chain can suffer reversible sulfenylation, decreasing its enzymatic activity (Figures 1 and 2 ). Complex I sulfenylation may suffer further irreversible oxidative modification resulting in its inactivation [75] . However, sensitive-cysteine residues in complex I can be saved from additional oxidation by Sglutathionylation [54] . Therefore, the S-glutathionylation of complex I restricts NADH production, lowering the electron flow through the respiratory chain, decreasing ROS over-production, and protecting this enzymatic complex from irreversible oxidation.

Cytochrome c oxidase (complex IV) is a crucial enzyme in the mitochondrial respiratory electron transport chain, containing fundamental cysteine residues that play basic roles in metal coordination required for the redox-linked proton pumping by the enzyme [76, 77] . Mitochondrial complex IV activity is reduced in brain tissue, fibroblasts, and blood platelets from AD patients [76] [77] [78] [79] . Additionally, oxidative phosphorylation is modulated through the redox change of the ATP synthase (complex V) by S-glutathionylation on Cys294 of the α-subunit placed in the F1 hydrophilic portion of the protein. In addition, Cys294 may form a disulfide bond with the neighboring Cys103 residue [80] . S-glutathionylation blocks nucleotide-binding to the complex resulting in a decrease in ATP generation. Thus, the oxidative modification of proteins in mitochondria can control ROS production and the bioenergetic ability of cells (Figures 1 and 2) .

Accumulation of β-amyloid inside brain mitochondria of AD patients interferes with mitochondrial fusion and fission, contributing to AD pathophysiology [81, 82] . Since neuronal bio-energetic demand relies on mitochondrial dynamics mediated by fission and fusion processes to generate new mitochondria, the redox interference with these pathways is crucial. Among SCCPs that participate in mitochondrial biogenesis, the integral membrane GTPases mitofusin 1 and dynamin-related protein-1 (Drp-1) are two well-known redox-regulated proteins (Figures 1 and 2) . Indeed, the fragmentation of mitochondria and the resulting loss of synapses in AD patients have been associated with S-nitrosylated Drp1 increased levels [83] [84] [85] . Redox micro-environmental conditions also regulate mitofusin's S-glutathionylation, which is required to induce mitochondrial hyperfusion [86, 87] , showing that mitochondrial SCCPs control the structure and biogenesis of mitochondria depending on the redox modulation of thiol groups in sensitive-cysteine residues of the involved proteins.

ROS overproduction can even alter the mitochondrial permeability transition pore (MPTP) through sulfenylation and S-glutathionylation modulating MPTP opening (Figures 1 and 2) , which requires the formation of disulfide bridges between distinct cysteine residues in the adenine nucleotide translocator (ANT), a member of MPTP that exports ATP from the mitochondrial matrix and imports ADP into the matrix [88] [89] [90] .

Many cytoplasmic proteins are modulated by cysteine redox modifications, including enzymes involved in glucose metabolism ( Figure 1 ). Glyceraldehyde-3-phosphate dehydrogenase, pyruvate kinase, phosphofructokinase, glucose 6-phosphate isomerase, glycogen phosphorylase, phosphoglycerate mutase 1, and phosphoglucomutase 2 need cysteine residues for their action [91] .

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been shown to be involved in AD pathophysiology [92] . Cytoplasmic GAPDH exists as a tetramer composed of four identical monomers containing a single sensitive-cysteine residue critical to the enzyme's catalytic function [93, 94] . This enzyme catalyzes the reversible phosphorylation of glyceraldehyde-3-phosphate involving the thiol group of Cys152 [92] . The four sensitivecysteine residues of GAPDH can be oxidized by hydrogen peroxide, reducing the stability of the protein resulting in monomers, dimers, and other denatured products [92] . Similarly, under pathological conditions, GSH can react with Cys152 contributing to the formation of disulfide bridges [92] . GAPDH has been found oxidized in AD brains [92] , though various investigations have indicated that S-glutathionylation of the enzyme is a mechanism to protect the protein against irreversible damage in the oxidizing environment of the AD brain [92] . Likewise, S-nitrosylation of Cys152 in GAPDH can be reversibly modified, inhibiting its dehydrogenase activity [92] [93] [94] . Interestingly, Cys152 in the enzyme's active site is required to induce apoptosis by oxidative stress [94] .

Protein tyrosine kinases (PTK) are a superfamily of enzymes containing conserved sensitive-cysteine residues ( Figure 1 ). For instance, protein tyrosine phosphatase 1B is redox-regulated by cysteine residues located in the catalytic core of the enzyme that are reversibly oxidized by hydrogen peroxide and by S-glutathionylation [95] . The result of these oxidative changes is an increase in tyrosine phosphorylation [95] . A subset of the PTK superfamily, including three of the ten Src family kinases and all four kinases of the FGFR family, have a sensitive-cysteine residue (Cys277) located in the catalytic domain. These PTK are vital enzymes in mammalian signal transduction pathways, and the reversible oxidative modification of Cys277 directly regulates PTK in the Src and FGFR families [96] . The aberrant protein phosphorylation in AD involves numerous examples of altered protein phosphorylation pathways, including protein tyrosine kinase (PTK). Several FGFs and their receptors (FGFR) are involved in the pathogenesis of AD [97] [98] [99] [100] [101] . Over-expression of FGF2 in AD patients repairs spatial learning, long-term potentiation, and neurogenesis, likely mediated by FGFR1-activated boosts in the OX-2 membrane glycoprotein (CD200). This OX-2 membrane glycoprotein regulates microglial activity and promotes neurite outgrowth and neuronal survival, suggesting a pivotal role of FGFRs in the crosstalk between degenerating neurons, microglia, and astrocytes [101] .

Reduced expression of the cysteine string protein α (CSPα) in forebrain areas in post-mortem samples from AD patients has been reported [102] . CSPα is a protein that regulates vesicle endocytosis participating in synaptic transmission and the maintenance of synapses [103] . The oligomerization of CSPα depends on a cysteine-rich "string" region of the protein for its attachment to synaptic vesicles [103] .

The frontal cortex in AD patients show significantly decreased synaptophysin concentrations than controls [104] . Synaptophysin plays a central role in the synaptic alterations found in AD, and its loss in the hippocampus correlates with cognitive decline in AD patients [105] . The role of this protein in the synaptic vesicle membranes is the formation of channels that depend on redox modifications in specific sensitive-cysteine residues. These sensitive-cysteine residues form disulfide bridges that connect with neighboring synaptophysin monomers ( Figure 1) . Synaptophysin cross-linking by disulfide bonds is modulated by an exquisite redox regulation, suggesting that native synaptophysin depends on the fine building of cysteine-associated disulfide bonds to create multimeric complexes in the precise phospholipid environment [106] .

More than 50% of AD patients show α-synuclein cumulation [107] . Though human α-synuclein does not include any cysteine residues [108] , tyrosine to cysteine substitution at vital places in the α-synuclein protein can raise dimer formation, accelerating protein aggregation and cellular toxicity of α-synuclein [109] . α-synuclein may also function as a chaperone-like protein in synergy with CSPα for assembling the SNARE (soluble NSF attachment protein receptor) complex [110] . This α-synuclein function involves linkage with synaptotagmin proteins, which have sensitive-cysteine residues in their configuration [110, 111] .

Familial AD is associated with APP, presenilin-1, and presenilin-2 gene mutations [112] . The demonstration that transgenic mice expressing familial human APP and presenilin mutations present significant features of the human AD [113] supports the amyloid cascade hypothesis [114] , suggesting that the abnormal processing of APP leads to the accumulation of Aβ peptides. Besides, the hyperphosphorylation of tau appears to be a crucial element for AD outcome [113, 114] .

Human presenilin-1 includes five cysteine residues [115] , three in transmembrane domains, and two uncovered to the cytosol. Cys410 and Cys419 in presenilin-1 transmembrane domain 8 can connect with Cys92 in transmembrane domain 1, contributing to the protein's conformational modifications enabling their reaction with the active site of γ-secretase [116] . These active cysteine residues may sustain the integrity and hydrophilic background necessary for the active center functionality [116] . Interestingly, familial AD patients have exhibited mutations in three of the five cysteine residues in presenilin-1, indicating the relevance of sensitive-cysteine redox deregulation in AD pathophysiology in early-onset cases [117, 118] (Figure 1 ). In contrast to presenilin-1, disulfide bonds between Cys14-Cys31 and Cys56-Cys65 in presenilin-2 are critical determinants of the 3D structure of the protein. These sensitive-cysteine residues are also crucial in regulating ryanodine receptor (RYR)-mediated Ca 2+ release [119] .

Sensitive-cysteine residues may participate in the palmitoylation of proteins, forming a thioester bond between the cysteine and palmitic acid, raising the hydrophobicity of the protein and promoting its integration into cellular membranes [120] . The withdrawal of APP from the ER requires two palmitoylation sites at Cys186 and Cys187 placed within the copper-binding part of APP, stabilizing the domain configuration and constructing disulfide bridges with Cys158 and Cys133, respectively [121] (Figure 1 ). Accordingly, increased APP palmitoylation enhances the non-amyloidogenic β-cleavage of APP [121] .

The imbalance between protein kinases and phosphatases leads to tau's hyperphosphorylation. The pathological aggregation of tau-forming paired helical filaments (PHFs) and neurofibrillary tangles also depends on the intermolecular cross-linking of Cys322 [122] . Different reactive species can cause cysteine oxidation in tau and microtubule-associated protein-2 (MAP2), changing the capacity of these proteins to interact with microtubules [123] ( Figure 1 ). Thus, augmented oxidative modification of sensitive-cysteine residues encountered in brain aging may contribute to tau and other protein aggregation in AD patients [122] .

Tau shows auto-acetylation activity through a couple of catalytic active cysteine residues in its microtubule-binding domain [124] (Figure 1 ). Tau proteins are nearly 99% attached to microtubules in adult neurons [124] , inhibiting their tau acetyl-transferase activity, blocking the functional cysteine residues connected to microtubules. Thus, microtubule detachment and the consequent activation of tau auto-acetyl transferase activity illustrate a pathological event which increases the pool of aggregation-prone tau species [124] . Consistent with this idea, acetyl-CoA levels are reported to be elevated in AD brains [124] , supporting the role of increased activity of tau acetyltransferase in the disease's progression. Indeed, tau aggregation inhibitors, such as methylthioninium, prevent tau filament formation via oxidation of cysteine residues in the tau repeat domain, preventing formation of disulfide bonds and maintaining the tau protein in a monomeric conformation [125] . Further, molecules that attach reactive cysteine residues of tau can stop neurofibrillary tangle-associated brain dysfunction [126] .

AD patients also show calcium (Ca 2+ ) disturbances attributed to Aβ-amyloid and NMDAR channel upregulation and mechanisms that implicate the prion protein [127, 128] . Intra-neuronal Ca 2+ levels depend on the balance between cytosolic Ca 2+ pumping into the ER lumen by the ER Ca 2+ ATPase (SERCA) pump and the discharge of Ca 2+ from the ER through the inositol 1,4,5-trisphosphate receptor (IP3R) and the RYR. RYR amplifies the IP3R-mediated clearance of Ca 2+ from ER, improving neuronal Ca 2+ signals [129] . IP3R and RYR receptors are the principal neuronal Ca 2+ channels regulated by the redox modification of sensitive-cysteine residues (Figure 1 ). S-nitrosylation and S-glutathionylation of various sensitive-cysteines control the closed state of the RYR1 complex resulting in a shift in Ca 2+ release to the cytoplasm [130] . In addition, IP3R contains numerous functional cysteine residues modified by ROS delivered in the ER and the mitochondria [131] . This receptor controls cytoplasmic Ca 2+ concentrations by modulating specific sensitive-cysteine residues, adjusting the active 3D conformation of the receptor [132] .

Previous results are relevant because IP3R levels are reduced in the hippocampus of AD patients, indicating substantial correlations with the senile plaque stage and neurofibrillary tangle pathology [133] . Additionally, Cys674 in SERCA can be oxidized by high glucose concentrations, preventing Cys674 inhibition by nitric oxide and hydrogen peroxide [134] , consequently contributing to Ca 2+ disturbances in AD ( Figure 1 ). Experiments with the skeletal muscle of hybrid rats showed that the SERCA pump is specifically oxidized in sensitive-cysteine residues during aging, suggesting age-related decrease in SERCA pump activity and, therefore, age-associated decrease in Ca 2+ -ATPase activity [135] .

The 3D structures of proteins are closely related to physiological and pathological consequences. Aging and other stressful conditions can disregulate the exquisite equilibrium among protein synthesis, folding, and degradation, contributing to protein aggregation. Protein folding depends on the primary sequence and cysteine protein content to form physiologically structural disulfide bridges under distinct redox situations [136] . Cysteine thiol groups of proteins can change between oxidized and reduced forms, contributing to their folding and unfolding configuration [137] . Many misfolded proteins contain disulfide bonds that can be irreversible [138] . In the case of SCCPs, the spontaneous folding process can be prolonged, requiring the formation of disulfide bonds [139] . Consequently, in vivo disulfide bridge-building is catalyzed by specific enzymes, such as PDI ( Figure 1 ) [140] . However, the normal PDI enzyme was found S-nitrosylated in brain specimens from patients with PD and AD [141] , facilitating further oxidative modifications of many other proteins and their accumulation in the ER, and compromising the chaperone function in protein folding [141] .

As previously mentioned, mitochondrial biogenesis is dependent on protein import from the cytoplasm by mitochondrial translocation routes. The mitochondrial import and assembly (MIA) pathway guides proteins to the intermembrane space (IMS), coupling the transport to folding and oxidation mechanisms that result in the covalent modification of the incoming protein predecessor incorporating disulfide bridges in the procedure [142] . Indeed, Mia40 (a thiol oxidase not belonging to the thioredoxin family) has its catalytic disulfide site arranged in a unique Cys-Pro-Cys motif, allowing the initially mixed disulfide formation between Mia40 and the substrate protein to drive the oxidative folding process that depends on the specific sensitive-cysteine residues to form the initial enzyme-substratemixed disulfide [143] . Therefore, Mia40 and other redox-active proteins, such as thioredoxin, glutaredoxin, and peroxiredoxin, participate in the redox-dependent chaperone-like mechanisms in the mitochondrial IMS, which are associated with specific sensitive-cysteine residues [143] (Figures 1 and 2 ).

The ubiquitin-proteasome machinery identifies and degrades impaired proteins, including misfolded and aggregated proteins [144] . The ubiquitin-proteasome machinery is a multistep pathway to recycling cellular proteins involving ATP-dependent activation of the ubiquitin protein that utilizes two enzymes (E1 and E2) to form ubiquitin-E2, binding to the target protein through the intermediation of the ubiquitin-protein ligase (E3) [145] . These phases depend on sensitive-cysteine residues that assemble successive thioester bonds concluding with the protein degradation in the proteasome [145] . Hence, the ubiquitinproteasome system depends on the redox modifications of the thiol groups of functional cysteine residues of the proteins involved in the pathway [146, 147] (Figure 1 ). Accumulation of ubiquitinated protein aggregates occurs during physiological brain aging, reaching pathological grades in various neurodegenerative disorders, such as AD [148] [149] [150] [151] . Similarly, a mouse model with spatial memory deficits and decreased brain proteasome activity showed increased levels of various proteins typically accumulated in AD brains [152] .

Cysteine proteases, including calpains, cathepsins, and caspases, can play important roles in AD pathophysiology [153] . Calpains are cysteine proteases involved in AD pathophysiology via reactivation mechanisms, including enriched intracellular Ca 2+ levels [154] . Moreover, Aβ peptides can activate calpains by increasing Ca 2+ concentrations contributing to neuronal cell disruption and death [125] . Calpain 1 and 2 activation depends on Ca 2+ , allowing the rearrangement of cysteine, histidine, and asparagine in the catalytic center [155] (Figure 1 ). Thus, Ca 2+ binding and the oxidation form of functional cysteines in the catalytic center are necessary for these proteases adequate activities [156] .

It has been shown that many proteins of the caspase family are transcriptionally elevated in AD, playing a role in AD pathophysiology [153] . Additionally, the S-nitrosylation of functional cysteines on the catalytic hub of caspase-3 can prevent apoptosis in AD [157] . Similarly, inhibitors of apoptosis (IAPs) are a family of proteins that control cell survival through the attachment to caspases inhibiting their catalytic actions [158] . The X-linked inhibitor of apoptosis (XIAP) protein is the principal cellular caspase inhibitor among the IAPs, and it is S-nitrosylated in various neurodegenerative diseases. Accordingly, exciting studies have shown significant increases in S-nitrosylated XIAP in brain specimens from PD, AD, and HD patients, potentially boosting apoptosis [159] (Figure 1 ).

Redox regulation of cysteine residues participates in the regulatory machinery of some gene transcription. For example, disulfide binds govern the building of the homotrimer of the heat shock transcription factor 1 (HSF1) that is translocated to the nucleus, activating the transcription of the heat shock proteins (Hsp) 70 and Hsp90. Hsp70 and Hsp90 have been shown to be involved in AD pathophysiology [160] . Under oxidative conditions, the molecular disulfide bridge prevents the action of HSF1, whereas under reducing conditions, these molecular links are split, and HSF1 cannot assemble the necessary trimer [160] ( Figure 1) .

AD brains show a decrease in the expression of the transcription factor Nrf2 and related pathways, interfering with diverse pathogenic processes, including Aβ and tau pathway deregulation [161] . Nrf2 modulates the expression of antioxidant proteins defending against oxidative injury and regulating the inflammatory response. Nrf2 is maintained in the cytoplasm by the Keap1 and Cullin-3 proteins, allowing the degradation of Nrf2 by ubiquitination [162] . Therefore, oxidative modification of vital sensitive-cysteines in Keap1 disrupts the Keap1-Cullin-3 transcription factor in the ubiquitination pathway, blocking Nrf2 ubiquitination. Thus, Nrf2 translocation into the nucleus allows interaction with the musculoaponeurotic fibrosarcoma (Maf) protein, activating the antioxidant response of many antioxidant genes and initiating their transcription [163] .

PD is an age-associated degenerative disorder distinguished by dopaminergic neurodegeneration in the substantia nigra of the brain [164] , also affecting the locus coeruleus that shows intraneuronal Lewy bodies composed of aggregates of α-synuclein and other proteins [165] intermixed with intracellular membranous organelles [166] . The localization of Lewy bodies and neuronal dopaminergic loss in PD suggested that α-synuclein aggregation and deposition are responsible for the disease. Nonetheless, Lewy bodies occur in the brains of asymptomatic, aged individuals [167] . Recent data shows that the accumulation of α-synuclein starts as micro-aggregates of the protein at the presynapse, impairing neurotransmitter vesicle trafficking and discharge in dopaminergic neurons [168, 169] . It has been proposed that Lewy bodies are formed to rescue neurons from the harmful outcomes of protein misfolding [170] .

Analogously to AD, only 5% of PD patients show mutations in a few genes, but most cases are sporadic [171] [172] [173] . The increasing proteomic intricacy of sporadic PD has been demonstrated in the last ten years, suggesting that very distinct biochemical pathways underlie this disorder's clinical manifestation and progression [5, [171] [172] [173] [174] . Oxidative impairment, reduced antioxidant ability, and mitochondrial dysfunction in the dopaminergic system have been shown to be involved in PD pathophysiology [175] [176] [177] .

Sporadic PD patients are associated with exposure to harmful compounds, including pesticides, such as paraquat, that impair mitochondrial complex I activity, inducing increased ROS production in neurons. Therefore, oxidative damage and individual mitochondrial genetic susceptibility contribute to PD pathophysiology, modifying the functionality of various proteins, including those of the bioenergetic metabolism [178] [179] [180] . Since ROS are products of dopamine metabolism in dopaminergic neurons modulating intermediary and bioenergetic metabolism [181] , cellular antioxidant machinery is indispensable for preserving redox homeostasis. Reduced concentrations of GSH appear to be the initial biochemical event recognized in the substantia nigra of premature PD individuals, correlating with PD severity and contributing to mitochondrial protein damage by oxidative insults [179] . Decreased GSH is the earliest indicator of associated mitochondrial complex I deficiency in dopaminergic neurons [178, 180] . Senescence can even participate in this process by accumulating oxidative injury, reducing antioxidant capacity, and decreasing mitochondrial bioenergetic capacity in the brain by protein oxidation mechanisms [182] [183] [184] [185] [186] [187] .

Recent investigations, including prioritized protein-protein relation networks, have revealed that proteins implicated in PD pathophysiology are involved mainly in the autophagy-lysosome and α-synuclein aggregation pathways [188] . These results reinforce the notion that the proteome in PD involves proteostasis failure by mechanisms that remain unknown. Global quantification of reduced and oxidized cysteine residues in physiological conditions has shown that, in the substantia nigra, the dopaminergic neurons are more oxidized than in the ventral tegmental region [189, 190] . Accordingly, some investigations support the view that oxidized cysteine residues in dopaminergic neurons of the substantia nigra in PD are more oxidized than in other areas [191] [192] [193] . These results suggest that the disturbance of the sensitive-cysteine proteome in PD plays a crucial function in its pathophysiology and advancement [1] [2] [3] [4] [5] 194] (Figures 1-3) .

As previously mentioned, proteostasis involves vital pathways that support protein homeostasis, including secretion via extracellular vesicles transporting diverse proteins among cells. Most cells can secrete small vesicles (exosomes and microvesicles) through various energy-dependent enzymes, which transport a complex mixture of proteins, nucleotides, and lipids [195] . Some analyses have shown that cells under oxidative stress sustain redox homeostasis by discharging cysteine-oxidized proteins through exosomes [195, 196] , such as the thiol-dependent peroxiredoxins [197] . The cysteine oxidized enzyme GAPDH can be released by exosomes [195] , implying membrane-bound and intraluminal protein mechanisms recognizing oxidized-cysteine residues in those proteins released by exosomes as a protective mechanism against oxidative damage. Similarly, microvesicle and exosome discharge rely on cytoplasmic Ca 2+ inflow through various Ca 2+ channels that contain functional cysteines triggered by oxidation [198] . For instance, exosome discharges under oxidative states depend on the particular thiol oxidation of IP3R, triggering calcium release from the ER to the cytoplasm [195] . Furthermore, Ca 2+dependent stimulation of calpains enables microvesicle building under the redox modification of sensitive-cysteines [199] (Figures 1-3 ).

The propagation of α-synuclein among neurons occurs through interactions with protein partners [200, 201] and via exosomes [202] . Inside the new neuron, α-synuclein fibrils are transported via axons to the nearest neurons or removed by the ubiquitin-proteasome system [203, 204] . DNAJC proteins are a subclass of the heat shock protein (HSP) family, mutations in which are associated with PD and other neurodegenerative diseases displaying Parkinsonism [205, 206] . CSPα is encoded by DNAJC5 and is abundantly localized in presynaptic vesicles [205, 206] . α-synuclein cooperates with CSPα to maintain the soluble SNARE complex assembly, which fuses vesicles with the target membrane [207] [208] [209] . CSPα includes a string-domain cysteine containing 13-15 heavily palmitoylated cysteines ( Figure 1 ). These palmitoylated cysteines are required for fusion goals, and modifications in this domain result in high molecular weight aggregates of CSPα, indicating that a set of palmitoylated cysteines is necessary for the assemblage of CSPα [210] .

Additionally, it has been shown that increased neuronal activity increases the release of tau through exosomes, promoting its propagation to neighboring neurons [211, 212] . Similarly, the spreading of tau by exosomes is raised in PD, implying that the dissemination of some proteins among neurons and between neurons and glial cells may play a role in progression of the illness [213] .

About 10% of patients with PD carry a mutation of the lysosomal enzyme glucocerebrosidase (GCase), which has a crucial role in Gaucher disease. However, only some carriers with GCase mutations develop PD [214, 215] . Moreover, some cases of idiopathic PD, without GCase mutations, show reduced enzyme concentrations [214, 215] , suggesting potential interactions between autophagy disturbances and α-synuclein accumulation in PD. Physiological wild-type GCase concentrations may ameliorate the phenotypes of Parkinson's disease models. GCase activation in pluripotent-stem-cell-derived dopaminergic neurons from sporadic PD subjects enhances the lysosomal role and diminishes the pathological aggregation of oxidized dopamine, glucosylceramide, and α-synuclein [216] . Analogous effects have been observed in patients harboring mutations in the genes encoding the GCase, LRRK2, DJ-1 (PARK7), or parkin, showing reduced GCase functionality [216] . Since mutations in GCase are a considerable genetic risk characteristic for PD, it was proposed that the activation of wild-type GCase is a probable restoring therapy for those cases of PD exhibiting impaired GCase activity, including familial instances of PD related to mutations in other cited proteins [216] .

GCase contains two disulfide bonds and three free thiolic groups in cysteine residues necessaries for the GCase activity, which serve as molecular modulators by glutathione [217] ( Figure 1) . Moreover, increased oxidized dopamine can regulate GCase acting at sensitivecysteines within its functional domain [218] , suggesting potential oxidative modification of sensitive-cysteine residues within GCase [217, 218] . Mass spectrometry analysis revealed 28 sensitive-cysteine residues, 23 in different GCase domains. Only Cys1465 is in the GTPase domain, and four (Cys2024, Cys2025, Cys2101, and Cys2114) are in the kinase domain of the protein [219].

The LRRK2 gene encodes the kinase enzyme leucine-rich repeat kinase 2 (LRRK2), also known as PARK8. The enzyme participates in cell autophagy and is present in the cytoplasm and the mitochondrial outer membrane. LRRK2 contains two essential cysteine residues for redox sensing [220] in the activation loop of the protein (Figure 1 ). Variants of this gene participate in PD evolution, and over one hundred additional mutations in this gene can raise the probability of PD [221] . In idiopathic PD patients, ROS can activate LRRK2 in dopaminergic neurons, suggesting that oxidative change of the LRRK2 protein potentially produces the phosphorylation of its Rab10 substrate, resulting in a sequence of events ending in neuronal death [222] . Therefore, LRRK2 mutations in familial PD cases increase activation of the protein and participate in the impairment of sporadic PD, indicating that the dysregulation of the activity of this protein is implicated in PD pathophysiology [222] .

Sporadic PD and LRRK2-related PD patients show decreased concentrations of 2hydroxybutyrate in CSF compared to controls [223] . This metabolite is derived from threonine or methionine metabolism via homocysteine and cystathionine, generating cysteine that reestablishes GSH levels and glutathione synthesis [223] .

The c-Abl protein plays a fundamental role in the cellular reaction against oxidative stress through sensing ROS [17, 224] . The protein has key sensitive-cysteine residues that mediate the formation of mixed disulfide bridges inhibiting c-Abl kinase activity (Figure 1) , indicating that the redox regulation of sensitive-cysteines in c-Abl is crucial for its kinase activity [225] . Recent studies show that c-Abl activation occurs in PD pathophysiology through the direct phosphorylation of α-synuclein, facilitating its accumulation and impeding its clearance by the ubiquitin-proteasome system [224] . Furthermore, parkin phosphorylation via c-Abl may inactivate the ligase activity of parkin, disrupting the proteasome function and enhancing dopaminergic neurodegeneration [224] . Consequently, c-Abl inhibitors have been proposed in the treatment of PD [224, 226] .

E3 ubiquitin ligase (Parkin) is a member of the RBR (RING-between-RING) ubiquitin ligase family that participates in ubiquitination mechanisms in proteasomes or lysosomes. RING0, RING1, RING2, and the in-between-RING (IBR) parkin subdomains are cysteinerich and bind to eight Zn 2+ ions [227] . Besides the catalytic Cys431, the redox reactive Cys268 and Cys323 identify impaired proteins on the outer mitochondria membrane mediating mitophagy [228, 229] . Parkin's sensitive-cysteines react with nitric oxide to generate S-nitrosylated parkin, which is increased in the brains of patients with Lewy body disease and PD because of interference with its neuroprotective function [230] (Figure 1 ). S-nitrosylation intervenes in parkin's vulnerability to dopamine oxidative injury by modifying two functional cysteines on the protein (Cys268 and Cys323), different from other cysteine-bearing enzymes in the same family [230] . S-nitrosylation of parkin enhances neuronal survival blocking apoptosis [231, 232] . This protein mutation is related to mitochondrial disturbances contributing to neuronal loss in PD [233] . Moreover, parkin can be transferred into the mitochondria under oxidative stress conditions without DJ-1 [227] , a cellular controller of ROS that protects mitochondria [234] .

6.1.6. Dopamine Transporter (DAT) DAT (dopamine transporter) is a transmembrane protein that is involved in the reuptake of the neurotransmitter dopamine at presynaptic terminals for further release. DAT contains eight sensitive-cysteines in the hydrophilic coils of the protein strategically positioned on both flanks of the cytoplasmic membrane. Specific cysteines are vital for preserving the adequate 3D conformation of the dopamine translocation transporter [235] , while other cysteines act in the S-palmitoylation of the protein via thioester bridges [236] ( Figure 1) . Hence, DAT controls dopamine signaling and contributes to dopamine homeostasis [237] .

The PARK7 gene encodes the DJ-1 protein, a cysteine protease whose mutations produce autosomal-recessive PD patients and which also participates in sporadic PD cases [238] . Patients with sporadic PD and AD show inactive forms of DJ-1 by oxidative impairment. DJ-1 includes three functional cysteines (Cys46, Cys53, and Cys106) sensitive to S-nitrosylation, but Cys106 redox-modification mainly modulates protein activity ( Figure 1) . Thus, S-nitrosylation of DJ-1 disturbs its antioxidant function in dopaminergic cells [239] . Additionally, Cys106 S-nitrosylation in DJ-1 inhibits transnitrosylation to PTEN, increasing its phosphatase action and reducing neuronal survival [240] .

6.1.8. ATP-Sensitive Potassium Channel (K-ATP Channel) K-ATP channels are complex proteins comprised of four potassium channels forming the pore and four sulfonylurea receptors (SUR1 or SUR2). Hydrogen sulfide (H 2 S) drives dopamine discharge through the redox change of two functional cysteines (Cys6 and Cys26) located in the N-terminal part of the regulatory subunit SUR1 of the protein complex [241, 242] (Figure 1 ). Since redox activation of K-ATP channels modulates dopamine excitability, these channels have been shown to be involved in particular susceptibility to dopamine neurodegeneration in PD models [243] .

In addition to the glutathione enzymatic system, sensitive-cysteine residues also regulate other critical antioxidant enzymes. Peroxiredoxins are a group of antioxidant enzymes with a reactive cysteine placed in the active zone that reduce cellular peroxides with the participation of the thioredoxin system (Figures 1 and 2) . Peroxiredoxin 2 (Prx2), the most significant member of the peroxiredoxin family in mammalian neurons, has been found to be more S-nitrosylated in the brains of PD than in controls [244] . Oxidative changes at Cys51 and Cys172 in Prx2 form an intermolecular disulfide bridge with another Prx2 protein, which can be reversed by the thioredoxin system. Nevertheless, additional oxidation of Cys51 and Cys172 can block Prx2 inhibition of the antioxidant function against hydrogen peroxide, contributing to dopaminergic neuronal death [244] .

Diverse Krebs cycle enzymes can suffer redox modifications in cysteine thiol groups. Some irreversible thiol-oxidative modifications can be deleterious for specific respiratory chain complexes resulting in additional ROS overproduction [75] . ROS, RNS, and RSS can modify mitochondrial complexes I, II, III, IV, and complex V of oxidative phosphorylation. Since complex I is the access point for electrons in the mitochondrial respiratory chain, the irreversible impairment of complex I enzymatic activity disrupts the electron flux, resulting in increased ROS generation and decreased ATP production (Figures 1 and 2) . Cysteine disulfide bridge construction between mitochondrial complex V subunits can significantly reduce ATP synthesis. Indeed, the disulfide link between Cys294 and Cys103 may interfere with its activity (Figures 1 and 2) . The redox transformation of Cys294 in the α-subunit by S-glutathionylation or S-nitrosylation may disrupt nucleotide-binding activity, reducing ATP synthesis [75] .

Specific functional cysteine residues can facilitate tau dimerization and oligomerization at the microtubule-binding domain of the protein involved in the tau-tau connection [126] . Cys322 can be redox modified, regulating tau self-assembly and permitting the pathological accumulation of tau into paired coiled filaments and neurofibrillary tangles that spread under oxidative situations [122, 245] (Figure 1 ). Vitamin B12 can interact with tau protein, blocking the reactive cysteines and interfering with tau aggregation [246] . Therefore, besides the imbalance between protein kinases and phosphatases that leads to tau fibrillation in neurodegenerative diseases, age-related and other disease-specific factors can increase cysteine oxidation in neuronal cells, increasing tau fibrillation. Peroxynitrite and H 2 O 2 may also cause sensitive-cysteine oxidation in tau and MAP2, disturbing their assembly with microtubules and permitting their pathological accumulation [123] (Figure 1) .

Tau protein can also catalyze its auto-acetylation through reactive cysteines in its microtubule-binding region (Figure 1) , increasing insoluble tau aggregation by intramolecular and intermolecular acetylation reactions [124] . Under physiological conditions, 99% of tau in mature neurons is attached to microtubules, inhibiting tau acetyl-transferase action through the blockage of sensitive-cysteines. Consequently, tau auto-acetyl transferase activity represents a pathological occurrence contributing to cytosolic tau aggregation [124] . Interestingly, methylthioninium can prevent the building of tau filaments and their harmful precursors via oxidative modification of the cysteine residues controlling the formation of disulfide bonds and retaining the tau protein in a monomeric conformation [125] . Accordingly, compounds that bind to tau sensitive-cysteine residues can prevent neurofibrillary tangle-associated brain disruption [126] . Therefore, the suggested cysteine-mediated impaired redox modulation of essential proteins implicated in PD may also impact the accumulation mechanisms that participate in the advancement of the disease.

α-synuclein mediates vital roles in neuronal synaptic terminals holding neurotransmitter generation and reuptake, vesicle storage and motility, and mitochondrial homeostasis. Therefore, misfolding and aggregation of α-synuclein result in mitochondrial and bio-energetic dysfunctions and raised oxidative deterioration in dopaminergic neurons. However, the exact consequences of α-synuclein misfolding, assemblage, and toxicity are unknown. ROS and RNS can cause α-synuclein aggregation by generating durable crosslinking dimers [247] . Because α-synuclein does not contain cysteine or tryptophan amino acids in its structure, oxidative changes must impact tyrosine and methionine residues, including diverse effects in protein fibrillation and folding [247] . Point mutations in αsynuclein may increase its assembly by changing the secondary structure of the protein that, in addition to ROS overproduction in the dopaminergic metabolism, may contribute to protein misfolding and aggregation [248] .

Oxidized α-synuclein is not optimally cleared by the ubiquitin-proteasome, contributing to its aggregation in neurons when GSH is reduced [170, 249] . The ubiquitin-proteasome mechanism itself is disturbed by sensitive-cysteine dysfunction in PD since this system utilizes the successive activity of diverse SCCPs. The E1 enzyme initiates an energyrich thioester bind that concerns the C-terminal glycine of the ubiquitin protein and the sensitive-cysteine of the functional center of the E1 enzyme, allowing the proteasome to identify and downgrade the ubiquitin-labeled protein [250] . E3 ubiquitin ligase (parkin) is modulated too by sensitive-cysteines participating in managing mitochondrial proteins by the proteasome [228] .

The proteasome also activates transcription regulators, such as the NF-κB signaling pathway. Specifically, oxidative stress activates the NF-kB pathway and suppresses autophagy and autophagy-dependent apoptosis, permitting the assembly and outspread of α-synuclein [251] . Recent results showed that α-synuclein accumulation in mitochondria is associated with defects in cellular respiration [252] . Moreover, α-synuclein interferes with mitochondrial fusion sensitive-cysteine proteins, such as mitofusin-1 (Mfn1), mitofusin-2 (Mfn2), and optic atrophy type 1 (Opa1), promoting mitochondrial fragmentation [253] (Figures 1-3) .

Amyotrophic lateral sclerosis (ALS) is a degenerative disease without effective therapy characterized by progressive motor neuron death of the motor cerebral cortex, brainstem, and spinal cord, associated with muscle atrophy and paralysis [254] . Like other neurodegenerative diseases, ALS can be sporadic (90%) or familial in patients with mutations in genes coding for proteins implicated in diverse cellular processes, including deficient RNA metabolism, glutamate excitotoxicity, disorders of membrane trafficking, endoplasmic reticulum (ER) stress, mitochondrial deficiencies, and protein misfolding and accumulation [255, 256] . The existence of motor neuronal inclusions developed by misfolded aggregated proteins is related to synaptic loss and neurodegeneration [254, 257] . Notably, subjects carry mutations in the genes encoding the antioxidant enzyme superoxide dismu-tase1 (SOD1), a zinc and copper metalloenzyme that dismutates superoxide radicals to hydrogen peroxide. Other proteins, such as the RNA-binding protein trans-active response DNA-binding protein (TDP43), and the fused in sarcoma/translocated in liposarcoma protein (FUS/TLS), have protein inclusions of SOD1, TDP43, and FUS. It is noteworthy that TDP43 is also accumulated in sporadic ALS and non-TDP43 familial ALS cases, excluding those with SOD1 mutations [258] .

Previous papers have shown evidence supporting the idea that ALS also causes deregulation of the sensitive-cysteine redox proteome [259] , suggesting that redox deregulation can modify the 3D structure of proteins leading to the formation of cysteine-mediated protein aggregation and inclusions into neurons [259] (Figures 1-3) .

SOD1 has various disulfide bonds and free cysteine residues that contribute to its 3D structure, interaction with other molecules, and activity [260] . There are multiple sites where SOD1 can be oxidized: sensitive-cysteine residues, Trp32, and the copper site histidines [260] . The human native SOD1 contains four sensitive-cysteines, Cys57 and Cys146, composing an intra-monomer disulfide bond, whereas Cys6 and Cys111 are free (Figures 1 and 2) . Structural disulfides play critical roles in stabilization and dimerization, as is the case for the Cys57-Cys146 disulfide, anchoring the zinc loop to the active center of the protein [261] and increasing its thermal stability [260, 261] . Cys111 is a pivotal regulator of SOD1 expression, folding, stability, assembly, and toxicity [259, 260] , and is set on the protein exterior close to the dimer interface allowing the formation of covalent disulfide bridges that can facilitate mutant SOD1 aggregates [262] . Sulphonylation of Cys111 in nonmutated SOD1 facilitates the enzyme adopting a Gly93Ala mutant-like 3D conformation that may interfere with fast axonal transport [263] . The S-thiolation of SOD1 protein with cysteine or GSH results in disulfide bridge formation with Cys111, changing some of the functional characteristics of the protein [259, 260] . In addition, S-glutathionylation on Cys111 may cause dissociation of wild type-and familial ALS mutant G93A-SOD1 dimers, triggering monomer formation and subsequent aggregation [261] . SOD1 can be palmitoylated to different extents at Cys6, Cys111, Cys57, and Cys146, in sporadic ALS cases [264, 265] (Figures 1 and 2) .

The Cys6 residue may also participate in the aggregation processes and the ubiquitylation of SOD1 mutants [259] . Cys6 can be palmitoylated in native SOD1 and familial ALS SOD1 mutants in motor neuronal cells through palmitoylation on reduced disulfides [264] . Reactive cysteines are implicated in SOD1 transport into the mitochondrial intermembrane space. Indeed, SOD1 transport is mediated by its copper chaperone redox-regulation, facilitating SOD1 maturation by forming disulfide bonds that allow its retention in the mitochondrial compartment [259] . Therefore, the redox modulation of sensitive-cysteine residues in SOD1 activity plays a significant role in the pathophysiology of ALS (Figures 1 and 2) . However, some SOD1 mutated patients present an absence of all four cysteine residues, which argues against an explicit function of cysteine residues in aggregation mechanisms in ALS [259] .

TDP43 contains six cysteines, Cys173, Cys175, Cys198, and Cys244, placed in the RNA recognition domains (RRM1 and RRM2), whereas Cys39 and Cys50 stand in the N-terminal part [266] . Upon oxidative challenge, full-length TDP43 is delocalized from the nucleus to the cytosol, forming oligomers and large aggregates [267, 268] . Oxidation of cysteine residues in RRM1 and RRM2 decreases protein solubility, developing intraand intermolecular disulfide bridges and contributing to the aggregation process [259, 267] ( Figure 1 ). Oxidative stress-inducing conditions participate in forming large aggregations of proteins and oligomer-dependent oxidation of accessible cysteine residues [259, 267, 268] , which are counteracted by reducing substances, such as high GSH levels [268] . However, a deficit of the GSH reservoir causes insolubilization and fragmentation of TDP43 in vitro [259] . The disruption of the physiological GSH/GSSG balance is crucial to activating the aggregation of mutant SOD1 and contributes to oxidizing wild-type SOD1 and TDP43, which are implicated in ALS pathophysiology through redox deregulation of the sensitive-cysteine proteome.

ALS and other neurodegenerative diseases have shown S-nitrosylation of PDIs (the covalent acquisition of a NO molecule to a cysteine thiol group) [67, 84, 269, 270] . In the post-mortem spinal cord from sporadic ALS and familial ALS patients, S-nitrosylated PDI concentrations are highly increased [271, 272] . When S-nitrosylation affects the PDI active site, the enzymatic activity of the enzyme is inhibited, resulting in reduction in its protective functions [273] (Figure 1 ). PDIs are members of the thioredoxin superfamily of proteins, usually localized in the ER, catalyzing the redox modification of disulfide bridges in proteins involved in protein folding [259] . PDIA1 and PDIA3 are upregulated in spinal cords cells from sporadic ALS patients [274] .

The essential function of sensitive-cysteine redox modification in ALS was confirmed through the discovery of PDI mutations in ALS patients [259] . Furthermore, PDIs cause misfolded protein inclusions in sporadic ALS patients [274] , interacting with TDP43 and FUS aggregates in tissues from ALS patients [275] . The redistribution of PDIs is related to a significant increase in their enzymatic action and to decline in inactive S-nitrosylated PDI compounds [259] . PDI accumulation at the ER-mitochondria intersection can initiate apoptosis through the mitochondrial exterior membrane permeabilization pore [276] . The impaired function of PDIs in these locations was recognized in rat models of HD and AD [259] , though comparable results in ALS examples have not yet been shown. These results suggest that PDI mutations and aberrant S-nitrosylation of PDIs are involved in pathophysiologic mechanisms in ALS.

In addition to activating the AMPK pathway by energy stress (i.e., changes in the metabolic AMP/ATP ratio), AMPK activity can be regulated by cellular redox status. AMPK is reversibly activated by the oxidation of sensitive-cysteines (Cys299/Cys303) in the AMPKα1 catalytic subunit without ATP depletion [277] (Figure 1) . Similarly, redox modification of AMPK activity has been shown by indirect redox effects on mitochondrial ATP production [278] . Hydrogen peroxide can activate AMPK by oxidation and S-glutathionylation at the Cys299/Cys304 residues of its α-subunit [277] but inhibits AMPK by oxidation at the Cys130/Cys174 residues of the α-subunit, promoting its aggregation and disrupting its interaction with upstream kinases [279] . These opposite redox regulations of AMPK depend on the relative abundance of nutrients and the antioxidant capacity of cells in different physiological and pathological conditions [280, 281] . Recent investigations have shown that cysteine depletion activates AMPK through calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2). Interestingly, the cysteinyl-tRNA synthetase (CARS), which plays a canonical role in protein translation, recognizes lack of cysteines and activates AMPK via the cysteine-CARS-CaMKK2-AMPKg2 system, adapting cell survival to nutri-ent deprivation [282] . Mitochondrial CARSs in human cells are involved in endogenous cysteine hydropersulfide (CysSSH) synthesis in vivo and even catalyze co-translational cysteine polysulfidation, which are implicated in the modulation of mitochondrial biogenesis and bioenergetics, playing a central role in redox signaling, cellular translation, and energy metabolism [283] .

High AMPK function has been observed in motor neurons expressing SOD1 or TDP43 mutants [259, 260] and in motor neuron cells of sporadic ALS and familial ALS patients [259] ( Figure 1 ). As mentioned above, thiol groups of cysteine residues in proteins can construct covalent disulfide bonds during the oxidative folding process conferring stability and functionality to the 3D structure of proteins [284] . The stability of intra-molecular and intermolecular disulfide links in proteins is achieved through interactions catalyzed by the PDI family of proteins in the oxidizing environment of the ER, or in proteins imported into the mitochondrial intermembrane space through the MIA pathway [259, 260] . Disulfide bonds are also formed in cytosolic proteins and chaperones, such as heat shock proteins [285] . Redox-sensitive cysteines are crucial for signal transduction, transcription factor binding to DNA such as Nrf-2 and NF-kB, receptor activity, and other vital cellular functions [286] .

Transgenic double mouse mutants for the human SOD1G93A without the endogenous FGF-2 gene, showed a significant disease onset delay and decreased motor performance impairment compared to mutant SOD1 mice with physiological FGF-2 concentrations [287] . Moreover, the survival of the double mouse mutants was significantly prolonged for two weeks. These findings are correlated with significant preservation of the number of motoneurons and decreased astrocytosis at the end phase of the disease, suggesting a significant protective effect of FGF-2 reduction. It has been suggested that up-regulation of other neurotrophic factors, such as ciliary neurotrophic factor (CNTF) and glial-derived neurotrophic factor (GDNF), are implicated in the proven protective effects in the ALS [287] . FGF-2 has four cysteine residues of which two exposed sensitive-cysteine residues (Cys78 and Cys96) may play a role in intermolecular disulfide-bridge formation with other proteins and macromolecules [288] (Figure 1) . Interestingly, FRF2 can upregulate system xcand potentially is responsible for some of its functional activities [289] .

Huntington's disease (HD) is an autosomal dominant condition distinguished by striatum and cerebral cortical neuronal loss. The aggregation of the mutant protein huntingtin (HTT) resulting from an expanded CAG tandem repeat (>35 repeats) in the HTT gene leads to an accumulation of the amino acid glutamine in the protein [290] . The disease pathophysiology is related to mitochondrial disturbance, oxidative stress, and excitotoxicity, derived from the protein accumulation and its interference with different cellular pathways [291] [292] [293] .

HTT suffers numerous PTMPs, including phosphorylation, acetylation, ubiquitination, sumoylation, proteolysis, and palmitoylation, which regulate subcellular localization, protein-protein relations, folding, aggregation, and degradation, and participate in numerous cellular functions, including endocytosis, vesicle/organelle transportation and recycling, autophagy, and DNA transcription [294] . Therefore, HTT mutants disturb diverse cellular pathways contributing to disease development and progression [294] .

Most research in HD pathophysiology and progression has been focused on the deleterious effects of mutant HTT on diverse cellular pathways. Insufficient attention has though been focused on the role of the sensitive-cysteine redox proteome as a mechanism participating in the etiology and advancement of the illness [294] (Figures 1-3 ).

Specific striatum impairment seems to be related to the binding of mutant HTT to the striatal-selective, small G protein Rhes (Ras homolog enriched in the striatum) [295] , which inhibits autophagy via Beclin-1 [296] . The Rhes protein is farnesylated at Cys263, which mediates the attachment of the protein to plasma and intracellular membranes [297, 298] ( Figure 1 ). Farnesylation is a post-translational modification consisting of the addition of a farnesyl group to proteins that facilitate protein-protein interaction and their association with membranes. Mutation of Rhes-Cys263 abolishes the sumoylation of mutant HTT and the neuropathology of HD [296] . Therefore, Rhes requires Cys263 redox regulation to maintain its physiological functionality (Figure 1 ). Beclin 1 is also a cysteine-rich protein that can be redox-regulated, forming part of a network that modulates autophagy and apoptosis [299] . In this network, Rubicon (RUN domain protein as Beclin 1 interacting and cysteine-rich containing) is a critical Beclin 1-binding partner, that also contains a cysteinerich region [299] localized to the late endosome/lysosome, but it negatively regulates autophagy [299, 300] . Therefore, Rhes directly interacts with HTT mutants and enhances cytotoxicity through increased sumoylation of the HTT protein, providing a potential explanation for the striatal selectivity of HD [295, 301] .

Sumoylation is a type of PTMP that participates in numerous cellular processes mediated by a small ubiquitin-like modifier (SUMO) connected to many different proteins. For example, SUMO-specific peptidase 3 (SENP3) is a particular redox-sensitive SUMO protease rapidly stabilized under oxidative stress by oxidation of its cysteine residues, blocking the ubiquitin-proteasomal degradation that occurs under physiological conditions [302] ( Figure 1) . Hence, ROS are necessary for autophagy initiation, while SENP3, also induced by ROS during starvation and autophagy, functions as a suppressor of autophagy [302] . DeSUMOylation of Beclin 1 restrained autophagy induction under basal conditions and starvation when SENP3 had been accumulated in response to ROS generation. Therefore, redox modification of SENP3 coupled with the deSUMOylation of Beclin 1 is critical in autophagy regulation [302] .

The striatum of human HD patients shows a significant reduction (85-90%) of cystathionine γ-lyase (CSE) levels, an enzyme that forms the gasotransmitter, hydrogen sulfide (H 2 S). Further, cystathionine β-synthase (CBS) and 3-mercaptopyruvate sulfurtransferase participate in H 2 S generation, a critical gasotransmitter in redox homeostasis [301] . According to the relative vulnerability of these brain areas to HD injury, CSE depletion is selective for the striatum and the cerebral cortex. Interestingly, mutant HTT attaches and inhibits the specificity protein 1 (Sp1), a transcription factor for CSE [301] . Overexpression of Sp1 and its co-activator, TATA box binding protein (TBP)-associated factor 4 (TAF4), inverts the decreased mRNA and protein concentrations of CSE, suggesting that mutant HTT inhibits the CSE transcription factor Sp1 [301] .

CSE can also generate cysteine from cystathionine ( Figure 1 ). Cysteine can generate H 2 S, activating many enzymes by attaching to the thiol groups of target proteins. Sulfhydration of parkin promotes its catalytic action and appears to provide neuroprotection to the striatum in PD [303] . H 2 S sulfhydrates Keap1, a repressor of Nrf2 that drives diverse enzymes in antioxidant pathways [304] . Indeed, the beneficial effects of cysteine administration in mouse HD models may be partially mediated through H 2 S modulation [305] .

The Golgi stress response to amino acid depletion and other stress-inducing conditions acts via the PKR-like ER kinase/activating transcription factor 4 (ATF4) pathway [306, 307] . One of the pathways regulated by ATF4 is the biosynthesis of cysteine through CSE upregulation, playing a vital role in redox homeostasis (Figure 1) . Thus, the involvement of the Golgi complex in neurodegenerative diseases, such as AD, ALS, and HD, can be related to deregulation of cysteine metabolism, including disturbance in the sensitive-cysteine redox proteome [306, 307] .

Brain transglutaminase activation may promote HD progression through promotion of cross-linking mutant HTT into aggregates [308, 309] . The transglutaminase inhibitor cystamine is neuroprotective in transgenic mouse HD models, increasing motor performance and survival. Cystamine inhibits transglutaminase activity by promoting the oxidation of Cys370 and Cys371, two sensitive-cysteine residues on the enzyme [310] (Figure 1 ). In addition, cystamine can decrease HTT aggregates, inhibit caspase 3, and increase glutathione levels [309] .

Mitochondrial and oxidative dysfunctions play significant roles in HD pathogenesis [311] . The antioxidant effects of cystamine have been shown in the brain of HD mouse models by increasing the concentration of cysteine [311] . The transcripts coding for proteins implicated in glutathione generation and function (gamma-glutamyl cysteine ligase, glutathione reductase), antioxidant systems (superoxide dismutase 2; SOD2), and thioldisulfide interaction (glutaredoxin) were identified in the mouse model of HD, suggesting that the restoration of sensitive-cysteine redox homeostasis plays a critical role in neuroprotection (Figures 1 and 2 ). SOD2 and glutaredoxin are essential enzymes for maintaining mitochondrial function, which has been shown to be disturbed in early HD [311] . Neuronal glutaredoxin is critical for enabling recovery of mitochondrial complex I activity after oxidative modification [311] (Figures 1 and 2) .

Oligomers of mutant HTT can form covalent cross-linking by different actions that include noncovalent polyglutamine-dependent reactions and oxidation [312] . Indeed, cysteine oxidation at specific sites can change protein 3D structure and function by affecting oligomerization state [312] . The N-terminus of HTT has various cysteine residues placed in all but the shortest N-terminal HTT components [312] . Oxidative modifications of these residues can control HTT function and thus are essential regulators of HD pathophysiology. Similar to Cys111 in human SOD1 [312] , the susceptibility of cysteine residues to oxidation depends critically on exposure of the peptide side chain to the redox environment (Figures 1 and 2) . The most N-terminal Cys115 residue of mammalian HTT is predisposed to oxidation because of the effects of the neighboring N-terminal histidine [312] . In addition, the N-terminal fragment of HTT, called N171, can form dimers with intermolecular disulfides. However, while the four cysteines in N171 HTT can intervene in the oligomerization, they do not act similarly. Cys115 and Cys119 are more susceptible to oligomerization than Cys137 and Cys158 [312] , suggesting that cysteine redox modification participates in HD pathophysiology by changing the mutant HTT 3D structure.

Regarding the mitochondrial respiratory transport chain and oxidative phosphorylation, a significant decline in mitochondrial complex IV activity and cytochrome aa3 amount has been described in HD brains [313] . Complex II-III and IV activities are also decreased in the caudate of HD persons [314, 315] , and supplementation with an irreversible blocker of succinate dehydrogenase (Complex II) reproduces the neurological pathology of HD [316, 317] . Likewise, a transgenic mouse model of HD indicated that complex IV defect and ROS overproduction precede neuronal loss [318] (Figures 1 and 2) . Moreover, HTT can bind the mitochondrial enzyme GAPDH as a function of disease-related glutamine repeats [319] , though the action of this enzyme was not changed in human HD brains [320] . Since the majority of these enzymatic complexes have sensitive-cysteine residues, it is suggested that a redox disturbance affects mitochondrial function in HD.

Palmitoylation of proteins is the principal protein-lipid modification in the brain [321] . It increases the hydrophobicity of proteins by adding a palmitic acid group onto a reactive cysteine of the protein through a thioester reaction, increasing the protein trafficking, stability, membrane association, and protein-protein relationships [322] . The S-palmitoylation is a reversible process and allows the active modification of protein to occur at the synapse, playing an essential function in neuronal survival [323, 324] .

Cys214 is susceptible to reversible palmitoylation in HTT, a response catalyzed by two palmitoyl acyltransferases called huntingtin-interacting protein 14 and 14-like (HIP14 and HIP14L) [294, 325] (Figure 1 ). However, some HD mouse models show that mutated HTT is less palmitoylated in the brain [325] . Using HD patient-derived lymphoblasts, it was demonstrated that mutant HTT palmitoylation was reduced with more polyQ repeats [294] . Indeed, auto-palmitoylation of HIP14 and HIP14L, and palmitoylation of numerous of their synaptic substrates, were downregulated in humanized HD mouse models and HD patient-derived lymphoblasts [294] . These findings suggest that reduced palmitoylation of mHTT in the brains of HD mouse models is not artifactual, but that aberrant palmitoylation of mutated HTT occurs in HD patients. Furthermore, it has been shown that deregulation of wild-type HTT palmitoylation in aging, combined with HTT mutations in HD patients, may be additive in disturbing palmitoylation protein levels [326] .

Frontotemporal dementia (FTD) is a frequent type of illness that occurs in patients below 65 years [327] due to progressive frontotemporal lobar degeneration (FTLD) of the brain [328] . FTD is a clinical spectrum of disorders with diverse pathological and genetic backgrounds. The principal histopathology involves tau, TDP43, and FUS proteins, and mutations in several genes have been implicated [328] [329] [330] . About 30-50% of FTLD cases are heritable [328, 329] , with most disease being due to mutations within three different proteins: progranulin (encoded by GRN), tau, and a GGGGCC hexanucleotide repeat expansion in C9orf72 (chromosome 9 open reading frame 72) [330] . FTD is less typically related to mutations in TARDBP (TAR DNA binding protein, encoding TDP43) and other genes [328] [329] [330] .

FTD syndromes can exist separately, or in combination with, other neurodegenerative disorders, including ALS and PD [328] . FTD develops in people with failure of one allele of the GRN gene encoding the protein progranulin, whereas loss of both alleles results in neuronal ceroid lipofuscinosis [331] . Progranulin is a full-length precursor glycoprotein formed by a signal peptide followed by 7.5 conserved tandem repeats of twelve cysteine-rich motifs processed by elastase and other proteases into six granulins (GRNs A-F) [331, 332] . Progranulin and GRN act as growth factors involved in various functions, including signal transduction, inflammation, proliferation, and wound repair [331, 332] . Progranulin plays a key role within neuronal lysosomes, a significant site for the production of GRNs by cysteine proteases, such as cathepsin L [333] . Specifically, as progranulin and GRNs have opposing functions in wound repair and inflammation, then conversion of progranulin to GRN by elastase acts as a molecular modulator of the host defense and wound repair [332] . Progranulin promotes neurite extension, neuronal cell survival, and differentiation [331] ; it is protective in various animal models of ALS, HD, PD, and AD, independently of their association or not with TDP43 deregulation [331] (Figures 1-3 ).

It is thought that decreased levels of progranulin cause FTD. However, the mechanism by which this protein deficiency affects neuronal function leading to neuronal death is not entirely understood. Interestingly, the pathogenic implication of two cysteine mutations (C521Y and C139R mutations) suggests that haploinsufficiency of progranulin/GRN is implicated in neurodegeneration [331, 332] . These two cysteine residues are conserved among vertebrate species and located within GRN E, and GRN F. Disulfide bridges are vital for progranulin and GRN folding and structure ( Figure 1) . Therefore, losing one conserved cysteine will disrupt one of the disulfide bridges affecting the protein 3D conformation. It has been shown that Cys521 and Cys139 mutations affect protein mobility under oxidative conditions but not under reducing conditions [332] .

These mutations affect progranulin cleavage by elastase, which is required to produce mature GRNs [331, 332] , suggesting that some mutations of cysteine residues disrupt the protein 3D structure affecting disulfide bond formation contributing to neuronal death ( Figure 1) . Therefore, in addition to low progranulin levels, the functionality of the proteins and their cleavage to generate mature GRNs are essential for normal neuronal function, and their disturbance can lead to neurodegeneration in FTD [332] .

Mitochondria are primary cellular organelles for ATP synthesis by oxidative phosphorylation. In addition to the proteins coded on the mitochondrial genome, including 13 proteins involved in the electron transport chain and oxidative phosphorylation, around 1500 proteins encoded in the nuclear genome are delivered as precursor molecules and transported into the mitochondria by the import machinery [334] . As previously mentioned, mitochondrial impairment is associated with aging and neurodegenerative diseases caused by chronic oxidative stress emanating from ROS generation [335] .

Some small mitochondrial proteins contain twin CX9C motifs ((CX9C)2) that participate in the transport of these proteins into the mitochondrial intermembrane space [336] . Mutations in two of these twin CX9C proteins, belonging to the mitochondrial coiled-coilhelix-coiled-coil-helix (CHCH) domain protein family, CHCHD2 and CHCHD10, have been linked to the pathogenesis of FTD, PD, ALS, and to diverse dominant inherited neurodegenerative diseases and sporadic neurodegenerative disorders [337] (Figures 1 and 2) . The role of the twin CX9C motifs from the CHCH domains is the building of two disulfide bridges to stabilize the helix-turn-helix fold. CHCH domains seem to hold different functions in binding to the mitochondrial import and assembly (Mia40) pathway in the IMS and proper folding of the protein. In CHCHD3, the temporary disulfide-bonded mediator with Mia40 is constructed mainly between Cys193 of CHCHD3 and the active site Cys55 in Mia40 [338] .

Mia40 has a critical redox-active disulfide bridge in a conserved cysteine-prolinecysteine region that promotes the steady folding of the substrate by introducing disulfide bonds, thus entrapping the substrates within the IMS (Figures 1 and 2) . Then, Mia40 is re-oxidized by the ETS translocation variant 1 (Erv1), a protein harboring two fundamental redox-active cysteine-x-x-cysteine pairs that transport the electrons from Mia40 to flavin adenine dinucleotide (FAD) [339] [340] [341] [342] . To achieve the disulfide interplay, Erv1 is oxidized by cytochrome c that donates the electrons through cytochrome c oxidase to oxygen in the respiratory electron chain [342] .

Modulation of cellular redox regulation at the protein level has not explicitly been addressed. The challenge is that slight changes may affect numerous metabolic and signaling pathways in the cell and even in the extracellular medium. Any substance that can modulate the redox proteome must, therefore, be regarded as medication with significant restorative ability but potential elevated secondary consequences due to its interference with highly controlled biological mechanisms. We have proposed the probable usefulness of NAC on the redox regulation of SCCPs involved in a broad spectrum of pathways implicated in neurodegenerative and psychiatric diseases [1] [2] [3] [4] [5] 29, 37, 187, [343] [344] [345] [346] [347] [348] [349] [350] [351] . NAC is a safe pro-substrate of cysteine that can repair redox disregulated states for diverse sensitive-cysteine-bearing proteins involved in many pathways (Figure 4 ). GSH is a sensitive-cysteine-bearing tripeptide, which is dependent on the cysteine/cystine pro-portion and the redox micro-environmental balance, regulating diverse protein functions by S-glutathionylation. 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).

NAC is a unique substance that has beneficial impacts in brain aging and neurodegenerative diseases, not only via classical antioxidant properties, but also, and even more importantly, enabling the repair and supervision of the cellular redox equilibrium through the modulation of the sensitive-cysteine network of intracellular and extracellular proteins (Figure 4 ) [1] [2] [3] [4] [5] . NAC is a membrane penetrable cysteine prodrug that regenerates total glutathione status and reduces excessive oxidized glutathione concentrations. Supplementation of GSH is of little value because it is oxidized in physiological conditions, having a remarkably brief half-life in human plasma (<3 min). Additionally, GSH has difficulty crossing cell membranes requiring elevated quantities to gain therapeutic concentrations [352] . On the other hand, there is adequate clinical proof that thiol-containing substances, such as NAC, can recover patients from toxic exposure to oxidative damage (e.g., acetaminophen overdose). NAC is effective in the established therapy of aged patients with obstructive pulmonary conditions, also showing significant chemo-preventive effects in lung cancer, with few harmful side effects even for longterm use [353, 354] . Furthermore, NAC treatments have a healthy impact on multiple other conditions, including oncological and cardiovascular diseases, ophthalmic diseases, HIV conditions, metal toxicity, cerebral ischemic and bleeding disorders, traumatic brain damage, and even neuropsychiatric disorders [355] [356] [357] [358] . NAC is a unique substance that has beneficial impacts in brain aging and neurodegenerative diseases, not only via classical antioxidant properties, but also, and even more importantly, enabling the repair and supervision of the cellular redox equilibrium through the modulation of the sensitive-cysteine network of intracellular and extracellular proteins ( Figure 4 ) [1] [2] [3] [4] [5] . NAC is a membrane penetrable cysteine prodrug that regenerates total glutathione status and reduces excessive oxidized glutathione concentrations. Supplementation of GSH is of little value because it is oxidized in physiological conditions, having a remarkably brief half-life in human plasma (<3 min). Additionally, GSH has difficulty crossing cell membranes requiring elevated quantities to gain therapeutic concentrations [352] . On the other hand, there is adequate clinical proof that thiol-containing substances, such as NAC, can recover patients from toxic exposure to oxidative damage (e.g., acetaminophen overdose). NAC is effective in the established therapy of aged patients with obstructive pulmonary conditions, also showing significant chemo-preventive effects in lung cancer, with few harmful side effects even for longterm use [353, 354] . Furthermore, NAC treatments have a healthy impact on multiple other conditions, including oncological and cardiovascular diseases, ophthalmic diseases, HIV conditions, metal toxicity, cerebral ischemic and bleeding disorders, traumatic brain damage, and even neuropsychiatric disorders [355] [356] [357] [358] .

NAC oral administration is rapidly absorbed with plasma concentrations of 16 µM and 35 µM after single doses of 600 mg/day and 1200 mg/day, respectively. The plasma half-life is estimated at 2.5 h, and no NAC is discernible 10-12 h following oral administration [359] . The terminal half-life of reduced NAC after oral administration is 6.25 h. It is quickly degraded and integrated into proteins with low concentrations of oxidized NAC detectable after several hours [345, 346] . Therefore, NAC is employed routinely in clinical practice, traveling across the blood-brain barrier (BBB), and immediately interacting with essential SCCPs in the brain, compensating brain-related aging and age-associated neurodegeneration [1] [2] [3] [4] [5] . NAC can likely repair redox imbalance by replenishing mitochondrial soluble and protein-linked thiols, restoring mitochondrial bio-energetic capability and adequate ROS concentrations, and decreasing the oxidative damage associated with brain aging.

Considering brain aging as the result of a progressive decline in the bio-energetic ability of neural cells accompanied by deregulation of metabolic homeostasis, involving the redox balance and proteostasis, no therapeutic or preventive interventions have achieved significant effects. Brain aging seems to depend on the inability of the mitochondria to support the bio-energetic capacity, which is mediated by the redox disturbance of the mitochondrial structure, biogenesis, and physiology associated with ROS overproduction [360] [361] [362] [363] [364] [365] [366] . Age-associated decline in the activity of various mitochondrial ROS-scavenging enzymes and the proliferation of mutations in mitochondrial DNA (mtDNA) may also influence cellular stem compartment. Thus, a vicious cycle may develop because of somatic mtDNA mutations, impaired mitochondrial respiratory chain activity, and oxidative phosphorylation deficiency, resulting in further ROS generation and accumulation of damaged proteins, lipids, and DNA [363] . Therefore, mitochondria play a crucial function in starting and driving the oxidative stress that causes the evolution of brain aging.

Numerous approaches have been used to neutralize the detrimental effects of brain aging. In particular, antioxidant molecules and dietary complements can potentially improve age-associated depletion of the bio-energetic ability of cells [367, 368] . The beneficial effects of caloric restriction in increasing neuron resistance to age-related disease has been demonstrated [367, 369] . Other approaches include anti-apoptotic agents targeting essential cellular proteins [370, 371] , while statins seem to prevent brain aging and age-associated neurodegenerative illness through different mechanisms ( Figure 4 ) [372] .

Modification of the redox state of critical functional cysteines in proteins by NAC administration has not been systematically examined previously. Redox modulation of SCCPs may illustrate numerous results of NAC treatment, including amelioration of metabolic processes, improvement of the immune system, and anti-aging effects [1] [2] [3] [4] [5] 373] . For example, the addition of NAC influenced the initiation and reduced the severity of early aging in Bmal1-deficient mice. Bmal1 is a circadian clock protein implicated in tissue homeostasis by the direct regulation of ROS, acting as a transcription factor of critical components of the circadian clock. NAC attenuated the development of the age-related phenotype of Bmal1−/− mice decreasing the development of cataracts and extending the animals' lifespan [374] . Studies in synaptic mitochondria from aged mice treated with NAC showed its anti-aging properties, increasing ATP levels through the activation of the mitochondrial complexes of the respiratory chain and oxidative phosphorylation, restoring GSH levels, and decreasing lipid and protein oxidation in presynaptic terminals [343] [344] [345] [346] [347] 365] .

Another beneficial action of NAC in brain aging is associated with glutamate uptake by astrocytes and neuron cells expressing the excitatory amino acid carrier-1 which can even transport the cysteine required for GSH biosynthesis. NAC reversed the GSH depletion and associated oxidative damage in a deficient mouse model of these carriers, suggesting that the excitatory amino-acid carrier-1 may be necessary for cysteine import and GSH biosynthesis in neuronal cells [375] . NAC can enhance the physiological function of mitochondrial complexes I, IV, and V in the synaptic mitochondria of old mice, likely restoring the oxidative damage of sensitive-cysteine residues in these proteins [343] [344] [345] [346] [347] .

In vivo experiments confirmed that these enzymatic functions were restored by regular NAC supplementation, with rising ATP and GSH concentrations, and reduction in lipid and protein oxidative damage in presynaptic terminals (Figure 4) [350, 351] .

Redox equilibrium is the primary process through which reactive species (ROS, RNS, and RSS) integrate the regulation of intracellular metabolic routes, principally mediated by SCCPs [1] . Reactive species also modulate transcription factors, such as nuclear factor kappa B (NF-kB), activator protein 1 (AP-1), and the inhibitor of nuclear factor-kappa B kinase (IKK), all of which contain redox-sensitive cysteine residues [376] . Specifically, NF-kB contains two redox-sensitive cysteine residues (Cys38 and Cys62) that are essential for its function [377, 378] , IKK contains Cys179 that participates in its catalytic kinase activity [379] , and the transcription factor AP-1 binds DNA under the control of redoxsensitive cysteines [380] . In this context, NAC can directly regulate common transcription factors both in vitro and in vivo [355] . NAC can suppress NF-kB in oxidative stress and clinical sepsis, diminishing the next cytokine generation [355, 381] . NF-kB is physiologically attached to its inhibitor (I-kB), preventing its nuclear transport. Dissociation of I-kB after its phosphorylation by IKK allows NF-kB to transport into the cellular nucleus [355] . Furthermore, NAC inhibits APP gene transcription in neuroblastoma cells by reducing the crucial activity of NF-kB ( Figure 4 ) [382] . These NAC actions are likely produced by their capacity to manage the reactive cysteines of the cysteine redox proteome [1] [2] [3] [4] [5] .

A potential restorative activity of NAC therapy is the inhibition of age-associated protein oxidation, misfolding, and aggregation by preventing sensitive-cysteine oxidative impairment related to aging. The 3D structures of proteins can suffer conformational changes when they accumulate oxidative damage [383] . The shift from a-helix to b-sheet is typical of amyloid and other protein accumulations. Structural modifications probably occur in proteins with redundant amino acid arrangements, such as polyglutamine in HD. Chaperones assist proteins in reaching their functional structure in physiological situations. However, in aging, the delicate equilibrium among protein synthesis, folding, and clearance can diminish, culminating in the aggregation of misfolded proteins. The assemblage of misfolded proteins contributes to the pathogenesis of age-associated neurodegenerative diseases, such as AD, PD, and HD, which NAC treatment can presumably repair. Cysteine-bearing compounds, such as GSH, NAC, and N-acetyl-cysteine amide (NACA) may preclude exosome production from oxidative and pro-inflammatory triggers through scavenging and preventing thiol-reactive substrates [195, 196] . NAC can correct exosome induction, arrangements, and actions to comparable levels of unexposed cells instead of completely inhibiting exosome signaling. Hence, NAC prevents oxidative shifts in exosome signaling without interrupting their physiological roles [195, 196] .

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] . Therefore, NAC administration can partially restore the age-associated accumulation of misfolded proteins, neutralizing one of the processes contributing to neurodegenerative disorder development (Figure 4) .

NAC may defend neurons via antioxidant properties and by controlling the redox standing of sensitive-cysteines in numerous proteins, thereby rejuvenating critical cellular pathways that support neural cell survival (Figure 4 ) [1] [2] [3] [4] [5] 187] . NAC can activate the Ras-ERK (extracellular signal-regulated kinase) pathway in vitro through non-antioxidant mechanisms, protecting neuronal cells from death in the absence of trophic factors. Since Ras proteins contain essential reactive cysteines, it was suggested that NAC could trigger Ras by its reducing capability [385, 386] . Some analyses showed that NAC could defend human neurons from the cerebral cortex against death induced by Aβ-amyloid 1−42 [187] , causing p35/Cdk5 activation and decreasing phosphorylation/deactivation of the MLK3-MKK7-JNK3 signaling pathway [reviewed in 1]. Cdk5 is a cyclin-dependent kinase triggered via p35, p25, and p39 [387] [388] [389] , acting as a neuronal-specific kinase implicated in cell preservation, axonal guidance, neuronal migration, and modulation of synaptic spine density [389] . Deregulation of Cdk5 function mediates the pathophysiology of diverse neurodegenerative illnesses, such as AD, ALS, PD, and HD [390] . Elevated Cdk5 activation by proteolytic cleavage of p35 to p25, through the calcium-activated protease calpain, can contribute to neurotoxicity. S-nitrosylation of Cys83 and Cys157 activates Cdk5 forming SNO-Cdk5, contributing to amyloid-β (Aβ) peptide-induced dendritic spine loss [390, 391] . Similarly, increased concentrations of SNO-Cdk5 have been observed in postmortem AD brains compared to control human brains, suggesting that S-nitrosylation of Cdk5 disturbs its enzymatic activity contributing to AD pathophysiology [390] . On the other hand, mixed lineage kinase 3 (MLK3) can be activated under ischemic stress. Its S-nitrosylation at the sensitive Cys688 residue contributes to its dimerization and activation, which has been implicated in brain ischemia/reperfusion damage [392] . However, NAC can inhibit the activation increase in MLK3 in the earlier phases of ischemia/reperfusion, indicating that MLK3 activation is again associated with ROS-mediated events following brain hypoxia [393] . Interestingly, MLK3 activation can phosphorylate other SCCPs, such as Pin1 [394] , increasing their catalytic activity and nuclear translocation [395] .

Finally, since the oxidative changes of sensitive-cysteines on proteins can influence exosome building and functions, thiol-protecting compounds, such as NAC, may protect against harmful disruption of extracellular vesicle mechanisms under pro-oxidant situations. NAC supplementation may repair vesicular physiology instead of impeding exosome processes [195] , repairing extracellular vesicle signaling by modulating the functional cysteine proteome. Hence, a probable restorative action of NAC supplementation in neurodegenerative diseases is the redox restoration of diverse structural, enzymatic, and signaling proteins implicated in extracellular vesicle formation and signaling. This contemporary notion reinforces the usefulness of NAC as a prophylactic and rejuvenating compound against brain aging and neurodegeneration, founded on the suggested restoration of the cysteine proteome [1-3].

NAC has been investigated in AD mice models [396, 397] . Nevertheless, studies in humans with neurodegenerative disorders are insufficient. Preclinical examinations have shown that NAC supplementation is helpful in AD murine models neutralizing oxidative impairment [396] [397] [398] and diminishing Aβ1-40 and Aβ1-42 concentrations [399] . Similarly, NAC can ameliorate the behavior of animals in the T-maze foot-shock escape procedure [400] . NAC supplementation to human APP/PS-1 knock-in mice preceding brain accumulation of Aβ, diminished protein and lipid oxidative damage, protein nitration, and raised glutathione peroxidase and reductase activities compared to normal aged animals [401] . Regular NAC therapy in human double mutant APP/PS-1 knock-in mice showed little gain in peptidyl-prolyl isomerase 1 (Pin1) amounts, likely reducing Aβ generated oxidative damage [401] . Pin1 has been implicated in AD [402] by oxidative modification in human AD brains [394] . The oxidation of Cys113 blocks Pin1 catalytic activity, and the substitution of Cys113 inactivates the Pin1 ability to isomerize with tau protein. Since Cys113-oxidized Pin1 is remarkably raised in the human AD brain compared to control aged people [394] , these results show another redox-disturbed critical sensitivecysteine residue in AD that can be regulated by NAC supplementation. Likewise, in vitro studies with NAC in cultured neuroblastoma cells affected APP metabolism by modifying β-secretase and γ-secretase actions and reduced phosphorylated tau concentrations in the absence of stressful conditions [403] .

AD postmortem cerebral cortex exhibited a substantial reduction in mitochondrial cytochrome c oxidase activity (mitochondrial complex IV). Moreover, cybrid cells transferred with mitochondria from AD platelets displayed complex IV deficiencies and increased ROS generation [404] . Accordingly, AD patients have mitochondrial DNA mutations [405] [406] [407] , indicating effects on mitochondrial DNA impairment and subsequent injury of neuronal bioenergetic ability [408] . Some investigations showed a reduction in mitochondrial mRNA encoding complex IV in AD patients' temporal cortex and hippocampus [409, 410] . In this regard, in vivo chronic oral NAC supplementation restored complex IV activity in synaptic mitochondria from old mice, decreasing mitochondrial lipids and oxidative protein damage [343, 344, 346] . This impact of NAC treatment correlated with a decrease in age-related memory deterioration in aged mice [350] . An exciting study investigated the effect of lipoic acid and NAC on fibroblasts obtained from people with AD, age-matched and young controls. Fibroblasts from AD patients displayed the most elevated amounts of oxidative damage, and both compounds diminished oxidative stress, apoptotic markers, and mitochondrial dysfunction compared to controls, suggesting that mitochondria could be a critical target of NAC supplementation [411] .

NAC supplementation (50 mg/kg/day in three divided daily doses) for 24 weeks in probable AD patients caused a beneficial trend on nearly every outcome measured, including the cystine-glutamate antiporter system, and marked progress in some cognitive tasks [412] . The cystine-glutamate antiporter system uptakes cystine, exerting beneficial effects, such as reducing β-amyloid stress, preventing oxidative-induced apoptosis, and improving sodium-dependent glutamate transporter activity [403, 413] . Another clinical study with moderate to late-stage AD patients improved neuropsychiatric tests following chronic NAC administration in addition to folic acid, vitamin B12, α-tocopherol, S-adenosyl methionine, and acetyl-L-carnitine [414] . Consistent with this, a patient with potential AD and hyperhomocysteinemia exhibited substantial clinical amelioration following NAC, vitamin B12, and folic acid administration [415] .

NAC can improve metabolic function, calcium signaling, protein misfolding, and proteostasis, all of which are implicated in AD progression. Indeed, NAC modified the oxidative damage of plasma proteins, such as transthyretin (TTR) by dose-dependent interaction with the reactive cysteine of the protein [416, 417] . TTR blocks the expression of AD phenotype in transgenic animal models, reducing cerebral Aβ deposition [418] .

A potential NAC action is the modulation of gene transcription and expression signals depending on the redox sensitivity of cysteine residues in the transcription factors themself. NAC can effectively modulate key transcription factors in vitro and in vivo [146] . Previous treatment of human neuroblastoma cells with NAC diminished β-amyloidogenesis induced by two oxysterols suggesting that this antioxidant can protect against cholesterol oxidation products modulating APP and β-secretase activity in the brain [419] .

Regarding the role of NAC in PD, a recent investigation showed that oxidative stressinducing conditions and toxic α-synuclein conditions resulted in c-Abl activation. NAC administration reversed this effect, accompanied by improvement in dopaminergic neuronal death and motor amelioration in a murine PD model [420] . Accordingly, recently a notable gain in DAT binding has been reported in the caudate and putamen of patients with idiopathic PD supplemented with NAC therapy. The investigation revealed substantial improvement in the dopaminergic system function estimated by DaTscan SPECT imaging and amelioration in the symptomatology of the disease [421, 422] . Moreover, in experimental PD models, peroxiredoxin 1 (Prx1) has also been implicated in dopaminergic neurodegeneration. NAC blocked the drug-induced oxidative damage of peroxiredoxins, suggesting that functional cysteines are critical in the susceptibility of peroxiredoxins to oxidative damage [423] . Therefore, complementing the known actions of NAC as a free radical scavenger and its ability to replenish GSH levels, it also can modify the thiolic groups of sensitive-cysteines in diverse proteins implicated in PD pathophysiology contributing to α-synuclein disruption [4, 5] .

The principal excitatory neurotransmitter in the mammalian CNS is the amino acid glutamate. Glutamate is removed from the synaptic space by the excitatory amino acid transporter (EAAT) lineage, formed of five components. EAAT1 and EAAT2 are expressed predominantly in glia, whereas EAAT3, EAAT4, and EAAT5 are mainly represented in neurons [424] . Dysfunction of these EAATs results in excitotoxicity associated with neurological conditions, such as ischemia, ALS, AD, and epilepsy [424] . EAAT3 also transports cysteine with higher affinity than other transporter family members [425] , and has been implicated in maintaining intracellular redox potential [426] . Indeed, EAAT3 deficient mice showed lowered concentrations of neuronal glutathione, augmented oxidative damage, and increased neuronal death in the dopaminergic neurons of the substantia nigra during aging [427] . Treatment of these mice with NAC, which was taken up by cells without the participation of EAAT3, rescued the phenotype, reinforcing the notion that EAAT3 activity is essential for the cysteine redox balance [426, 427] . The particular high-affinity and transportation of acidic amino acids by EAATs concerns the positively charged residue in the EAAT3, which is preserved in all EAATs [426] . The replacement of Arg447 by cysteine in EAAT3 transforms the protein from an acidic amino acid carrier to one that carries neutral amino acids [426] .

NAC prevented mitochondrial dysfunction in a rat HD model [428] . Injection of rats with 3-nitropropionic acid (3-NP) induced an irreversible inhibition of mitochondrial complex II, resulting in oxidative damage in both striatum and cortical synaptosomes of treated animals [429] . Pretreatment with NAC starting two hours before 3-NP injection rescued the animals against oxidative injury resulting in a significant reduction in striatal lesions [429] . In addition, ROS overproduction and lipid peroxidation in the mitochondria of 3-NP-injected animals was associated with decreased thiol levels and SOD activity in mitochondria in rats not treated with NAC. Nevertheless, NAC treatment could reverse 3-NP-induced mitochondrial disturbances and behavioral deficiencies [428, 429] , indicating a potential therapeutic impact of NAC in this HD model, likely mediated by a restoration of the sensitive-cysteine redox proteome. Moreover, chronic NAC administration reduced the onset and progression of motor deficits in a transgenic mouse model of HD [305] . These transgenic mice showed reduced mitochondrial respiratory ability in the striatum, which was rescued by NAC treatment associated with ameliorating oxidative damage in mitochondria [305] .

Likewise, NAC increased the glutamate neurotransmitter in HD mice in a glutamate transporter-dependent way [430] . However, the glutathione redox system was unchanged, suggesting that NAC may act by independent antioxidant mechanisms [430] , contributing to in vivo modifications in glutamate transporter proteins in HD mice and HD patients. We propose that supplementing diets with NAC can compensate for low levels of cysteine, reducing oxidative stress and restoring, at least partially, the enzymatic activity of sensitivecysteine proteins, such as CSE in HD, which in turn generate H 2 S, cysteine, and other thiol products, such as cysteamine and CoA.

NAC administration can reduce oxidative damage and mitochondrial dysregulation in human neuroblastoma cells (SH-SY5Y) with the G93A-SOD1 mutation, and delay the beginning of motor injuries and enhance survival in G93A-SOD1 mutated mice [431, 432] . NAC treatment of patients with ALS partially modified the course of the disease [433] . A randomized, double-blind, and controlled trial showed that NAC produced a moderate, statistically non-significant gain in survival without proof of a decline in disease advancement. The amount employed was much lower than the dose utilized in clinical trials with beneficial effects for other CNS disorders [434] . Likewise, the impact of NAC may rely on the variety of ALS expressed since NAC was able to enhance survival in subgroups of patients with limb onset illness compared to those with bulbar onset [433] .

Future studies will be necessary regarding the essential role of sensitive-cysteine residues in maintaining protein structures and functions and the implications of NAC for diverse clinical and empirical conditions. Here, we emphasize the uniqueness of NAC as the best compound that is presently extensively employed in clinical routine, that can traverse the blood-brain barrier (BBB), and can potentially modulate key SCCPs in the brain, counteracting significant harmful effects of brain aging and associated neurodegeneration [435] . Current studies have revealed the beneficial influence of NAC on the dopamine system related to improving clinical outcomes in PD [421, 422] . In these studies, DaTScans before and after therapy with NAC over 90 days measured dopamine transporter (DAT) binding. The results demonstrated a notable improvement in caudate and putamen DAT binding in PD patients supplemented with NAC compared to the control group. Additionally, clinical manifestations, estimated through the unified Parkinson's disease rating scale score, were remarkably enhanced in the NAC patients [421, 422] .

Determining cysteinet deregulation in clinical samples from complex neurodegenerative disorders is technically challenging. However, a recent prospective study has shown that plasma GSH concentrations and mental function decreased after two years in patients with mild cognitive impairment (MCI) [436] . The redox status of human serum albumin, the major protein in the blood, seems to play a predominant role in redox regulation through its thiol group in the redox-sensitive Cys34 [437] . Moreover, it can serve as a prognostic biomarker of oxidative damage in chronic degenerative diseases [437, 438] . Cys34 in albumin exists in equilibrium between reduced and oxidized forms, and their ratio, in addition to GSH levels, may indicate the progression of oxidative damage in complex degenerative diseases [438] . For example, albumin in oxidized form is about 35% under healthy physiological conditions, but it can rise to 70% after oxidative insults [439] . Interestingly, albumin Cys34 redox modification in vivo is mainly due to the interaction with the cysteine/cysteine ratio [439] , and therefore with GSH/GSSG ratio without the involvement of any enzymatic support. An analogous mechanism is conceivable in many SCCPs under physiological and pathological conditions. Thus, differential cysteine labeling investigations and global label-free proteomics analyses in blood, CSF, and brain samples seem to be necessary to comprehend the function of the cysteinet disturbance in aging and age-related neurodegenerative disorders (Figure 3 ).

The number of SCCPs implicated in different neurodegenerative diseases is continuously increasing, and their participation in each specific disorder needs to be investigated without delay. For example, the involvement of APOE4 and tau variability in the development of dementia in PD has recently been recognized [440] . Additionally, the role of oxidative damage and disulfide bond formation in tau [441] and other SCCPs are critical triggering mechanisms leading to neurodegenerative disorders and pathogenic progression factors. Therefore, NAC may offer an effective therapeutic strategy to decrease the generation and spread of pathological proteins [442] .

We propose large-scale investigations in selected groups of people over 40 years of age with decreased blood GSH levels, comorbidities, and/or MCI by supplementing the diet with low doses (between 1800-3000 mg/week) of NAC, a promising and well-tolerated therapeutic agent suitable for long-term use. Although MCI has been designed to recognize a prodromal stage of dementia, identifying cognitive impairment in the preclinical or earliest clinical stages is not easy. Clinical trials aiming to decrease oxidative injury remain unsuccessful for age-associated neurodegenerative diseases, and GSH scavengers can even impair the physiological function of ROS, RNS, and RSS. However, early intervention is essential for preventing the evolution of age-related neurodegeneration because pathological brain damages have been found years or even decades before the cognitive decline was clinically evident. Therefore, we propose an early intervention using low doses of NAC supplementation in people over 40 years of age with comorbidities (e.g., diabetes, hypertension, obesity, and cardiovascular disturbances) or presenting disruption in GSH and albumin redox ratios. NAC can likely maintain and repair redox homeostasis dysregulation by replenishing free (cysteine/glutathione) and protein-linked thiols to restore mitochondrial bio-energetic ability and biogenesis. NAC can be regarded as an effective compound due to its capacity to regulate a diversity of vital proteins from many cellular processes. Consequently, its doses must be accurately investigated. Much work remains to be done to examine the redox modulation implicated in the principal pathways in neural cells and its role in degenerative disorders. However, NAC can play an essential role in preventing age-associated oxidative dysregulation in the brain.

Cellular cysteine network (Cysteinet): Pharmacological intervention in brain aging and neurodegenerative diseases. In Frontiers in Clinical Drug Research-Central Nervous System; Atta-ur-Rahman

Cysteine network (CYSTEINET) dysregulation in Parkinson's disease: Role of N-acetylcysteine

A natural antidote for Alzheimer's disease. Alzheimers Dis. Dement

Potential role of N-acetyl-cysteine in the cysteine proteome in Parkinson's sisease?

Proteomic complexity in Parkinson's disease: A redox signaling perspective of the pathophysiology and progression

Collapse of redox homeostasis during aging and stress

The cys sense: Thiol redox switches mediate life cycles of celular proteins

Quality control in the endoplasmic reticulum protein factory

Molecular chaperone functions in protein folding and proteostasis

The chemical biology of molecular chaperones-Implications for modulation of proteostasis

A quantitative tissue-specific landscape of protein redox regulation during aging

Global profiling of distinct cysteine redox forms reveals wide-ranging redox regulation in C. elegans

Quantitative reactivity profiling predicts functional cysteines in proteomes

Glutathione metabolism and its selective modification

The cysteine proteome. Free Radic

The oxidative environment and protein damage

Redox regulation of protein kinases

Regulation of proteasome assembly and activity in health and disease

ATP hydrolysis by the proteasome regulatory complex PAN serves multiple functions in protein degradation

The mechanism of ubiquitin activating enzyme

Ubiquitin-proteasome pathway and cellular responses to oxidative stress. Free Radic

Distinct cysteine cesidues in Keap1 are required for Keap1-dependent ubiquitination of Nrf2 and for stabilization of Nrf2 by chemopreventive agents and oxidative stress

Molecular mechanism of cellular oxidative stress sensing by Keap1

Cysteine sulfenylation directs IRE-1 to activate the SKN-1/Nrf2 antioxidant response

Modulation of proteostasis by transcription factor NRF2 and impact in neurodegenerative diseases

Small molecules govern thiol redox switches

Dynamic redox balance directs the oocyte-toembryo transition via developmentally controlled reactive cysteine changes

N-acetyl-cysteine in schizophrenia: Potential role on the sensitive cysteine proteome

N-acetylcysteine in psychiatric disorders: Possible role of cysteinet deregulation

Endogenous oxidative stress: Relationship to aging, longevity and caloric restriction

The role of oxidative damage and stress in aging

Is the oxidative stress theory of aging dead?

Redox analysis of human plasma allows separation of pro-oxidant events of aging from decline in antioxidant defenses. Free Radic

In sickness and in health

Mechanisms of altered redox regulation in neurodegenerative diseases-Focus on S-glutathionylation

Oxidative stress in the progression of Alzheimer disease in the frontal cortex

N-acetylcysteine protecs against age-related decline of oxidative phosphorylation in liver mitochondria

Differential cysteine labelling and global label-free proteomics reveals an altered metabolic state in skeletal muscle aging

A protein homeostasis signature in healthy brains recapitulates tissue vulnerability to Alzheimer's disease

Neural mechanisms of ageing and cognitive decline

Beneficial effects of dietary restriction on cerebral cortical synaptic terminals: Preservation of glucose transport and mitochondrial function after exposure to amyloid β-peptide and oxidative and metabolic insults

Global cysteine-reactivity profiling during impaired insulin/IGF-1 signaling in C. elegans identifies uncharacterized mediators of longevity

The efficiency of protein compartmentalization into the secretory pathway

Cysteine-mediated redox signaling: Chemistry, biology, and tools for discovery

The basics of thiols and cysteines in redox biology and chemistry. Free Radic

Proteotoxic stress and ageing triggers the loss of redox homeostasis across cellular compartments

Synapse alterations in the hippocampal-entorhinal formation in Alzheimer's disease with and without Lewy body disease

Abeta oligomer-induced aberrations in synapse composition, shape, and density provide a molecular basis for loss of connectivity in Alzheimer's disease

Microtubule-associated protein tau (tau) is a major antigenic component of paired helical filaments in Alzheimer disease

-42) is a major component of cerebrovascular amyloid deposits: Implications for the pathology of Alzheimer disease

Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production

A specific amyloid-beta protein assembly in the brain impairs memory

Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

Expanding the functional diversity of proteins through cysteine oxidation

High-throughput identification of catalytic redox-active cysteine residues

Diverse functional roles of reactive cysteines

Alzheimer's disease: The protective effects of ApoE2 and E3. J. Alzheimer's Dis

Structural differences between apoE3 and apoE4 may be useful in developing therapeutic agents for Alzheimer's disease

A mechanism for the neuroprotective effect of apolipoprotein E: Isoform-specific modification by the lipid peroxidation product 4-hydroxynonenal

S-nitrosylation of ApoE in Alzheimer's disease

Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families

Common gene variants, mortality and extreme longevity in humans

Apolipoprotein E and Alzheimer's disease

Human apoE isoforms differentially regulate brain amyloid-β peptide clearance

Contribution of cysteine 158, the glycosylation site theonine 194, the amino-and carboxy-terminal domains of apolipoprotein E in the binding to amyloid peptide β (1-40)

The autolysis of human HtrA1 is governed by the redox state of its N-terminal domain

Redox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseases

Mitochondrial dysfunction is a trigger of Alzheimer's disease pathophysiology

The Alzheimer's disease mitochondrial cascade hypothesis

Role of mitochondrial amyloid-β in Alzheimer's disease. J. Alzheimer's Dis

Deconstructing mitochondrial dysfunction in Alzheimer disease

Early deficits in synaptic mitochondria in an Alzheimer's disease mouse model

Synaptosomal mitochondrial dysfunction in 5xFAD mouse model of Alzheimer's disease

Quantitative proteomics of synaptic and nonsynaptic mitochondria: Insights for synaptic mitochondrial vulnerability

Redox regulation of mitochondrial function with emphasis on cysteine oxidation reactions

Mitochondria in Alzheimer's disease

Cytochrome c oxidase is decreased in Alzheimer's disease platelets

Reduced platelet cytochrome c oxidase activity in Alzheimer's disease

Cortical cytochrome oxidase activity is reduced in Alzheimer's disease

Cytochrome c oxidase and mitochondrial F1F0-ATPase (ATP synthase) activities in platelets and brain from patients with Alzheimer's disease

Accumulation of amyloid precursor protein in the mitochondrial import channels of human Alzheimer's disease brain is associated with mitochondrial dysfunction

Mitochondrial amyloid-beta levels are associated with the extent of mitochondrial dysfunction in different brain regions and the degree of cognitive impairment in Alzheimer's transgenic mice

Dynamic organelles in disease, aging, and development

Redox modulation by S-nitrosylation contributes to protein misfolding, mitochondrial dynamics, and neuronal synaptic damage in neurodegenerative diseases

Mitochondrial dynamics fusion, fission, movement, and mitophagy in neurodegenerative diseases

The intracellular redox state is a core determinant of mitochondrial fusion

Mitochondrial hyperfusion during oxidative stress is coupled to a dysregulation in calcium handling within a C2C12 cell model

The adenine nucleotide translocase: A central component of the mitochondrial permeability transition pore and key player in cell death

Glutathionylation of adenine nucleotide translocase induced by carbon monoxide prevents mitochondrial membrane permeabilization and apoptosis

Role of critical thiol groups on the matrix surface of the adenine nucleotide translocase in the mechanism of the mitochondrial permeability transition pore

Application of iTRAQ reagents to relatively quantify the reversible redox state of cysteine residues

Oxidatively modified glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and Alzheimer disease: Many pathways to neurodegeneration

The diverse functions of GAPDH: Views from different subcellular compartments

GAPDH: A common enzyme with uncommon functions

Regulation of protein tyrosine phosphatase 1B in intact cells by S-nitrosothiols

Direct and specific inactivation of protein tyrosine kinases in the Src and FGFR families by reversible cysteine oxidation

Changes in protein kinases in brain aging and Alzheimer's disease. Implications for drug therapy

Distribution of fibroblast growth factor receptor-1 (FGFR-1) and FGFR-3 in the hippocampus of patients with Alzheimer's disease

Evidence for neuroprotective effects of acidic fibroblast growth factor in Alzheimer disease

Dysregulated fibroblast growth factor (FGF) signaling in neurological and psychiatric disorders

Fibroblast growth factor signalling in the diseased nervous system

Evidence that the presynaptic vesicle protein CSPalpha is a key player in synaptic degeneration and protection in Alzheimer inverted question marks disease

Cysteine string protein (CSP) and its role in preventing neurodegeneration

Frontal cortical synaptophysin in Lewy body diseases: Relation to Alzheimer's disease and dementia

Loss of the presynaptic vesicle protein synaptophysin in hippocampus correlates with cognitive decline in Alzheimer disease

The multisubunit structure of synaptophysin

Neuropathology of Parkinson's disease

Structure of membrane-bound α-synuclein studied by site-directed spin labeling

Tyrosine-to-cysteine modification of human α-synuclein enhances protein aggregation and cellular toxicity

α-synuclein in Parkinson's disease. Cold Spring Harb

Synaptotagmins: Why so many?

Cloning of a gene bearing missense mutations in early-onset familial Alzheimer's disease

Alzheimer's disease mutations in APP but not γ-secretase modulators affect epsilon-cleavage-dependent AICD production

Neurodegeneration induced by β-amyloid peptides in vitro: The role of peptide assembly state

A nine transmembrane domain topology for presenilin 1

Deducing the transmembrane domain organization of presenilin-1 in γ-secretase by cysteine disulfide crosslinking

Identification of new presenilin gene mutations in early-onset familial Alzheimer disease

Contribution of presenilin transmembrane domains 6 and 7 to a water-containing cavity in the γ-secretase complex

Presenilins regulate the cellular activity of ryanodine receptors differentially through isotype-specific N-terminal cysteines

Palmitoylation of amyloid precursor protein regulates amyloidogenic processing in lipid rafts

Structure of the Alzheimer's disease amyloid precursor protein copper binding domain: A regulator of neuronal copper homeostasis

Oxidation of cysteine-322 in the repeat domain of microtubule-associated protein T controls the in vitro assembly of paired helical filaments

Cysteine oxidation of Tau and microtubule-associated protein-2 by peroxynitrite

The microtubule-associated tau protein has intrinsic acetyltransferase activity

The fuzzy coat of pathological human Tau fibrils is a two-layered polyelectric brush

Toxic tau oligomer formation blocked by capping of cysteine residues with 1,2-dihydroxybenzene groups

Expansion of the calcium hypothesis of brain aging and Alzheimer's disease: Minding the store

Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia

Enhanced ryanodine receptor recruitment contributes to Ca 2+ disruptions in young, adult, and aged Alzheimer's disease mice

Nitric oxide, NOC-12, and S-nitrosoglutathione modulate the skeletal muscle calcium release channel/ryanodine receptor by different mechanisms. An allosteric function for O 2 in S-nitrosylation of the channel

Isoform-and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species

Subtype-selective regulation of IP3 receptors by thimerosal via cysteine residues within the IP3-binding core and suppressor domain

Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer's disease neurofibrillary pathology

High glucose oxidizes SERCA cysteine-674 and prevents inhibition by nitric oxide of smooth muscle cell migration

Quantitative mapping of oxidation-sensitive cysteine residues in SERCA in vivo and in vitro by HPLC-electrospray-tandem MS: Selective protein oxidation during biological aging

Protein folding guides disulfide bond formation

Role for cysteine residues in the in vivo folding and assembly of the phage P22 tail spike

The two faces of protein misfolding: Gain-and loss-of-function in neurodegenerative diseases

Protein folding, misfolding, and refolding of therapeutic proteins

Disulfide bonds as probes of protein folding pathways

S-nitrosylated protein disulphide isomerase links protein misfolding to neurodegeneration

Disulfide formation in the ER and mitochondria: Two solutions to a common process

Mia40 targets cysteines in a hydrophobic environment to direct oxidative protein folding in the mitochondria

Hassles with taking out the garbage: Aggravating aggresomes

Protein degradation by the ubiquitin-proteasome pathway in normal and disease states

Regulation of ubiquitin-conjugating enzymes by glutathione following oxidative stress

Oxidative stress responses involve oxidation of a conserved ubiquitin pathway enzyme

Relationship between amyloid-beta and the ubiquitin-proteasome system in Alzheimer's disease

Role of the ubiquitin proteasome system in Alzheimer's disease

Perturbations of ubiquitin-proteasome-mediated proteolysis in aging and Alzheimer's disease. Front

The ubiquitin system in Alzheimer's disease

Long-term proteasome dysfunction in the mouse brain by expression of aberrant ubiquitin

The role of cysteine proteases in Alzheimer disease

Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease

A Ca 2+ switch aligns the active site of calpain

Calpains-An elaborate proteolytic system

Finazzi-Agro, A. S-nitrosylation regulates apoptosis

IAP proteins: Blocking the road to death's door

S-nitrosylation of XIAP compromises neuronal survival in Parkinson's disease

Two distinct disulfide bonds formed in human heat shock transcription factor 1 actin opposition to regulate its DNA binding activity

Nrf2: A dark horse in Alzheimer's disease treatment

Nrf2 degradation by the ubiquitin proteasome pathway is inhibited by KIAA0132, the human homolog to INrf2

Redox mechanisms involved in the selective activation of Nrf2-mediated resistance versus p53-dependent apoptosis in adenocarcinoma gastric cells

Neuropathology of Parkinson disease

Diagnostic criteria for Parkinson disease

situ architecture of neuronal α-Synuclein inclusions

A critical reappraisal of current staging of Lewy related pathology in human brain

The synaptic pathology of α-synuclein aggregation in dementia with Lewy bodies, Parkinson's disease and Parkinson's disease dementia

Is cell death primary or secondary in the pathophysiology of idiopathic Parkinson's disease? Biomolecules

Lewy-body formation is an aggresome-related process: A hypothesis

Genetic and environmental risk factors in Parkinson's Disease

Genetics of Parkinson's disease. Cold Spring Harb

The role of monogenic genes in idiopathic Parkinson's disease

The genetic architecture of Parkinson's disease

The oxidant stress hypothesis in Parkinson's disease: Evidence supporting it

Oxidative stress in Parkinson's disease

Toxin models of mitochondrial dysfunction in Parkinson's disease

Anatomic and disease specificity of NADH CoQ1 reductase (complex I) deficiency in Parkinson's disease

Parkinson's disease: A disorder due to nigral glutathione deficiency?

Origin and functional consequences of the complex I defect in Parkinson's disease

Thiol chemistry and specificity in redox signaling. Free Radic

Age-dependent impairment of mitochondrial function in primate brain

Brain protein oxidation in age-related neurodegenerative disorders that are associated with aggregated proteins

Excess brain protein oxidation and enzyme dysfunction in normal aging and in Alzheimer disease

Lipid peroxidation in aging brain and Alzheimer's disease. Free Radic

Age-related increase in oxidized proteins in mouse synaptic mitochondria

Antioxidants inhibit the human cortical neuron apoptosis induced by hydrogen peroxide, tumor necrosis factor alpha, dopamine and beta-amyloid peptide 1-42

Prioritizing Parkinson's disease genes using population-scale transcriptomic data

Oxidant stress evoked by pacemaking in dopaminergic neurons is attenuated by DJ-1

Single-cell redox imaging demonstrates a distinctive response of dopaminergic neurons to oxidative insults

Redox imbalance in Parkinson's disease

Thiol-redox signaling, dopaminergic cell death, and Parkinson's disease

Redox mechanisms in neurodegeneration: From disease outcomes to therapeutic opportunities

Cysteine oxidation and redox signaling in dopaminergic neurons physiology and in Parkinson's disease

Redox-dependent thiol modifications: Implications for the release of extracellular vesicles

Microvesicles: ROS scavengers and ROS producers

Cysteine oxidation targets peroxiredoxins 1 and 2 for exosomal release through a novel mechanism of redox-dependent secretion

Redox regulation of cardiac calcium channels and transporters

Calcium influx is a determining factor of calpain activation and microparticle formation in platelets

Inclusion formation and neuronal cell death through neuron-to-neuron transmission of α-synuclein

ADP-ribose) drives pathologic α-synuclein neurodegeneration in Parkinson's disease

Exosomal cell-to-cell transmission of alpha synuclein oligomers

Assembly-dependent endocytosis and clearance of extracellular alpha-synuclein

Neuron-to-neuron transmission of alpha-synuclein fibrils through axonal transport

DNAJC proteins and pathways to parkinsonism

DnaJ/Hsp40 family and Parkinson's disease

α-synuclein cooperates with CSPα in preventing neurodegeneration

DNAJ proteins in neurodegeneration: Essential and protective factors

A multifunctional player in exocytosis, endocytosis, and vesicle recycling

Neurons export extracellular vesicles enriched in cysteine string protein and misfolded protein cargo

Proteostasis of tau. Tau overexpression results in its secretion via membrane vesicles

The release and trans-synaptic transmission of Tau via exosomes

CNS tau efflux via exosomes is likely increased in Parkinson's disease but not in Alzheimer's disease. Alzheimer's Dement

The role of glucocerebrosidase in Parkinson disease pathogenesis

Glucocerebrosidase and its relevance to Parkinson disease

A modulator of wild-type glucocerebrosidase improves pathogenic phenotypes in dopaminergic neuronal models of Parkinson's disease

X-ray structure of human acid-βglucosidase, the defective enzyme in Gaucher disease

Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease

Kinetic, mechanistic, and structural modeling studies of truncated wild-type leucine-rich repeat kinase 2 and the G2019S mutant

The dynamic switch mechanism that leads to activation of LRRK2 is embedded in the DFGψ motif in the kinase domain

Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology

LRRK2 activation in idiopathic Parkinson's disease

Changes to intermediary metabolites in sporadic and LRRK2 Parkinson's disease demonstrated by proton magnetic resonance spectroscopy

c-Abl and Parkinson's disease: Mechanisms and therapeutic potential

The functional role of cysteine residues for c-Abl kinase activity

The c-Abl inhibitor, Radotinib HCl, is neuroprotective in a preclinical Parkinson's disease mouse model

ROS-dependent regulation of parkin and DJ-1 localization during oxidative stress in neurons

Parkin mediates proteasome-dependent protein degradation and rupture of the outer mitochondrial membrane

Parkin structure and function

Nitrosative stress linked to sporadic Parkinson's disease: S-nitrosylation of parkin regulates its E3 ubiquitin ligase activity

S-nitrosylation regulates mitochondrial quality control via activation of parkin

Oxidation of the cysteine-rich regions of parkin perturbs its E3 ligase activity and contributes to protein aggregation

The role of parkin in familial and sporadic Parkinson's disease

The Parkinson's disease DJ-1 is neuroprotective due to cysteine-sulfinic acid-driven mitocondrial localization

Transport-dependent accessibility of a cytoplasmic loop cysteine in the human dopamine transporter

Palmitoylation mechanisms in dopamine transporter regulation

Plasma membrane monoamine transporters: Structure, regulation and function

Mutations in the DJ-1 gene associated with autosomal recessive early-onset parkinsonism

Roles of distinct cysteine residues in S-nitrosylation and dimerization of DJ-1

Transnitrosylation from DJ-1 to PTEN attenuates neuronal cell death in Parkinson's disease models

Effects of thiol-modifying agents on KATP channels in guinea pig ventricular cells

Molecular mechanism for H 2 S-induced activation of K ATP channels

Endogenous hydrogen peroxide regulates the excitability of midbrain dopamine neurons via ATP-sensitive potassium channels

S-nitrosylation of peroxiredoxin 2 promotes oxidative stress-induced neuronal cell death in Parkinson's disease

Vitamin B12 inhibits Tau fibrillization via binding to cysteine residues of Tau

α-synuclein misfolding and Parkinson's disease

Glutathione decreases in dopaminergic PC12 cells interfere with the ubiquitin protein degradation pathway: Relevance for Parkinson's disease?

Protein quality control and elimination of protein waste: The role of the ubiquitin-proteasome system

Nuclear Factor-κB dysregulation and α-synuclein pathology: Critical interplay in the pathogenesis of Parkinson's disease. Front. Aging Neurosci

Pathogenic alpha-synuclein aggregates preferentially bind to mitochondria and affect cellular respiration

Alpha-synuclein physiology and pathology: A perspective on cellular structures and organelles

The changing scene of amyotrophic lateral sclerosis

State of play in amyotrophic lateral sclerosis genetics

Emerging mechanisms of molecular pathology in ALS

Synapse loss in anterior horn neurons in amyotrophic lateral sclerosis

Gains or losses: Molecular mechanisms of TDP43-mediated neurodegeneration

Cysteine modifications in the pathogenesis of ALS

The biophysics of superoxide dismutase-1 and amyotrophic lateral sclerosis

Molecular recognition and maturation of SOD1 by its evolutionarily destabilized cognate chaperone hCCS

Amyotrophic lateral sclerosis: From current developments in the laboratory to clinical implications

Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS

Palmitoylation of superoxide dismutase 1 (SOD1) is increased for familial ALS-linked SOD1 mutants

S-acylation of SOD1, CCS, and a stable SOD1-CCS heterodimer in human spinal cords from ALS and non-ALS subjects

TDP-43 proteinopathy and ALS: Insights into disease mechanisms and therapeutic targets

Redox signaling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking

Structural insights into the multi-determinant aggregation of TDP-43 in motor neuron-like cells

S-nitrosylated protein disulfide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis

Aberrant protein S-nitrosylation in neurodegenerative diseases

Protein disulfide isomerase and the endoplasmic reticulum in amyotrophic lateral sclerosis

Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis

Nitrosative stress in the ER: A new role for S-nitrosylation in neurodegenerative diseases

Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis

Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase

Proapoptotic activities of protein disulfide isomerase (PDI) and PDIA3 protein, a role of the Bcl-2 protein Bak

Exposure to hydrogen peroxide induces oxidation and activation of AMP-activated protein kinase

Mitochondria-derived ROS activate AMP-activated protein kinase (AMPK) indirectly

A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation

Regulation and function of AMPK in physiology and diseases

AMPK, metabolism, and vascular function

CARS senses cysteine deprivation to activate AMPK for cell survival

Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics

Disulfide bonds in ER protein folding and homeostasis

Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 2. Protein misfolding and ER stress

Radical-free biology of oxidative stress

Prolonged survival and milder impairment of motor function in the SOD1 ALS mouse model devoid of fibroblast growth factor 2

Structural basis of conserved cysteine in the fibroblast growth factor family: Evidence for a vestigial halfcystine

Functional upregulation of system xc-by fibroblast growth factor-2

The Huntington's Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes

Oxidative stress in Huntington's disease

Biochemical abnormalities and excitotoxicity in Huntington's disease brain

Excitotoxic neuronal death and the pathogenesis of Huntington's disease

Rescue of aberrant huntingtin palmitoylation ameliorates mutant huntingtin-induced toxicity

Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity

Rhes, a striatal-selective protein implicated in Huntington disease, binds beclin-1 and activates autophagy

Autophagy and polyglutamine diseases

Cargo recognition failure is responsible for inefficient autophagy in Huntington's disease

The Beclin 1 network regulates autophagy and apoptosis

Protein Structure, Function and Regulation. Cells 2021

Neurodegeneration in Huntington's disease involves loss of cystathionine γ-lyase

A fine-tuning mechanism underlying self-control for autophagy: deSUMOylation of BECN1 by SENP3

Sulfhydration mediates neuroprotective actions of parkin

Hydrogen sulfide protects against cellular senescence via S-sulfhydration of Keap1 and activation of Nrf

N-Acetylcysteine improves mitochondrial function and ameliorates behavioral deficits in the R6/1 mouse model of Huntington's disease

Transcriptional control of amino acid homeostasis is disrupted in Huntington's disease

Golgi stress response reprograms cysteine metabolism to confer cytoprotection in Huntington's disease

Transglutaminase action imitates Huntington's disease: Selective polymerization of Huntingtin containing expanded polyglutamine

Cystamine increases L-cysteine levels in Huntington's disease transgenic mouse brain and in a PC12 model of polyglutamine aggregation

Cystamine and cysteamine as inhibitors of transglutaminase activity in vivo

Cysteamine protects neurons from mutant Huntingtin toxicity

Cysteine oxidation within N-terminal mutant huntingtin promotes oligomerization and delays clearance of soluble protein

Regional mitochondria respiratory activity in Huntington's disease brain

Mitochondrial defect in Huntington's disease caudate nucleus

Mitochondrial function and parental sex effect in Huntington's disease

Behavioral pathology induced by repeated systemic injection of 3-nitropropionic acid mimics the motor symptoms of Huntington's disease

Chronic mitochondrial energy impairment produces selective striatal degeneration and abnormal choreiform movements in primates

Mitochondrial dysfunction and free radical damage in the Huntington R6/2 transgenic mouse

Huntington and DRPLA proteins selectively interact with the enzyme GAPDH

Oxidative damage and metabolic dysfunction in Huntington's disease: Selective vulnerability of the basal ganglia

Palmitoylation of intracellular signaling proteins: Regulation and function

Protein palmitoylation in neuronal development and synaptic plasticity

Protein palmitoylation in the development and plasticity of neuronal connections

Role of palmitoylation of postsynaptic proteins in promoting synaptic plasticity

Palmitoylation of huntingtin by HIP14 is essential for its trafficking and function

Higher levels of protein palmitoylation in the frontal cortex across aging were associated with reference memory and executive function declines

Update on frontotemporal dementia

Progranulin, lysosomal regulation and neurodegenerative disease

Frontotemporal lobar degeneration: Pathogenesis, pathology and pathways to phenotype

The genetics and neuropathology of frontotemporal lobar degeneration

Progranulin: A new avenue towards the understanding and treatment of neurodegenerative disease

Pathogenic cysteine mutations affect progranulin function and production of mature granulins

Intracellular proteolysis of progranulin generates stable, lysosomal granulins that are haploinsufficient in patients with frontotemporal dementia caused by GRN mutations

The protein import machinery of mitochondria-a regulatory hub in metabolism, stress, and disease

Mitochondrial diseases: The contribution of organelle stress responses to pathology

Protein import and oxidative folding in the mitochondrial intermembrane space of intact mammalian cells

Twin CHCH Proteins, CHCHD2, and CHCHD10: Key molecules of Parkinson's disease, amyotrophic lateral sclerosis, and frontotemporal dementia

Targeting and import mechanism of coiled-coil helix coiled-coil helix domain-containing protein 3 (ChChd3) into the mitochondrial intermembrane space

Forming disulfides in the endoplasmic reticulum

The mitochondrial disulfide relay system: Roles in oxidative protein folding and beyond

To Mia or not to Mia: Stepwise evolution of the mitochondrial intermembrane space disulfide relay

Mitochondrial thiol oxidase Erv1: Both shuttle cysteine residues are required for its function with distinct roles

N-acetylcysteine elicited increase in complex I activity in synaptic mitochondria from aged mice: Implications for treatment of Parkinson's disease

Therapeutic potential of N-acetylcysteine in age-related mitochondrial neurodegenerative diseases

N-acetyl-cysteine in the treatment of Parkinson's disease. What are we waiting for

N-acetylcysteine elicited increase in cytochrome c oxidase activity in mice synaptic mitochondria

Hypothesis: Can N-acetylcysteine be beneficial in Parkinson's disease?

Cysteinet dysregulation in muscular dystrophies: A pathogenic network susceptible to therapy

Nacetylcysteine (NAC) in schizophrenia resistant to clozapine: A double blind randomised placebo controlled trial targeting negative symptoms

Acetylcysteine delays age-associated memory impairment in mice: Role in synaptic mitochondria

N-acetylcysteine protects against age-related increase in oxidized proteins in mouse synaptic mitochondria

Reduced intravenous glutathione in the treatment of early Parkinson's disease

N-Acetylcysteine for lung cancer prevention

Inhibition of urethan-induced lung tumors in mice by dietary N-acetylcysteine

The chemistry and biological activities of N-acetylcysteine

A review of clinical usefulness (an old drug with new tricks)

Mechanisms of N-acetylcysteine in the prevention of DNA damage and cancer, with special reference to smoking-related end-points

The role for N-acetylcysteine in the management of COPD

Pharmacokinetics and bioavailability of oral acetylcysteine in healthy volunteers

The biological clock: The mitochondria

Oxidative damage to DNA during aging: 8-hydroxy-2 -deoxyguanosine in rat organ DNA and urine

Protein oxidation and aging

Depletion of cytosolic GSH decreases the ATP levels and viability of synaptosomes from aged mice but not from young mice

Impairment of mitochondrial oxidative phosphorylation in the brain of aged mice

Age-related changes in glutathione and lipid peroxide content in mouse synaptic mitochondria: Relationship to cytochrome c oxidase decline

Modification of brain aging and neurodegenerative disorders by genes, diet, and behavior

Effects of turmeric on blood and liver lipoperoxide levels of mice: Lack of toxicity

Dietary restriction and 2-deoxyglucose administration reduce focal ischemic brain damage and improve behavioral outcome: Evidence for a preconditioning mechanism

A synthetic inhibitor of p53 protects neurons against death induced by ischemic and excitotoxic insults, and amyloid beta-peptide

p53 inhibitors preserve dopamine neurons and motor function in experimental parkinsonism

Simvastatin strongly reduces levels of Alzheimer's disease α-amyloid peptides Aβ42 and Aβ40 in vitro and in vivo

Interfering with the reactive cysteine proteome in COVID-19

Antioxidant N-acetyl-L-cysteine ameliorates symptoms of premature aging associated with the deficiency of the circadian protein BMAL1

Neuronal glutathione deficiency and age-dependent neurodegeneration in the EAAC1 deficient mouse

How the redox state regulates immunity. Free Radic

Cysteine 38 in p65/NF-κB plays a crucial role in DNA binding inhibition by sesquiterpene lactones

Thioredoxin regulates the DNA binding activity of NF-κB by reduction of a disulphide bond involving cysteine 62

Inhibitors of NF-κB signaling: 785 and counting

Activator protein-1: Redox switch controlling structure and DNA-binding

Is there a place for N-acetylcysteine in the treatment of septic shock?

N-acetyl-L-cystein downregulates beta-amyloid precursor protein gene transcription in human neuroblastoma cells

Protein misfolding and degenerative diseases

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

Prevention of PC12 cell death by N-Acetylcysteine requires activation of the Ras pathway

Biophysical and proteomic characterization strategies for cysteine modifications in Ras GTPases

p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5

A brain-specific activator of cyclin-dependent kinase 5

Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death

S-Nitrosylation activates Cdk5 and contributes to synaptic spine loss induced by beta-amyloid peptide

S-nitrosylation of cyclin-dependent kinase 5 (cdk5) regulates its kinase activity and dendrite growth during neuronal development

S-nitrosylation of mixed lineage kinase 3 contributes to its activation after cerebral ischemia

Antioxidant N-acetylcysteine and AMPA/KA receptor antagonist DNQX inhibited mixed lineage kinase-3 activation following cerebral ischemia in rat hippocampus

Pin1 cysteine-113 oxidation inhibits its catalytic activity and cellular function in Alzheimer's disease

Mixed-lineage kinase 3 phosphorylates prolyl-isomerase Pin1 to regulate its nuclear translocation and cellular function

N-acteylcysteine alleviates oxidative damage to central nervous system of ApoE-deficient mice following folate and vitamin E-deficiency

Pilot study of the reducing effect on amyloidosis in vivo by three FDA pre-approved drugs via the Alzheimer's APP 5 untranslated region

Dietary supplementation with 3-deaza adenosine, N-acetyl-cysteine, and S-adenosyl methionine provide neuroprotection against multiple consequences of vitamin deficiency and oxidative challenge

RNA therapeutics directed to the non coding regions of APP mRNA, in vivo anti-amyloid efficacy of paroxetine, erythromycin, and N-acetyl-cysteine

The antioxidants α-lipoic acid and N-acetylcysteine reverse memory impairment and brain oxidative stress in aged SAMP8 mice

Potential in vivo amelioration by N-acetyl-L-cysteine of oxidative stress in brain in human double mutant APP/PS-1 knock-in mice: Toward therapeutic modulation of mild cognitive impairment

Oxidative modification and down-regulation of Pin1 in Alzheimer's disease hippocampus: A redox proteomics analysis

N-acetyl-L-cysteine protects SHSY5Y neuroblastoma cells from oxidative stress and cell cytotoxicity: Effects on beta-amyloid secretion and tau phosphorylation

Cybrids in Alzheimer's disease: A cellular model of the disease

A mitochondrial DNA deletion in normaly aging and in Alzheimer brain tissue

A mitochondrial DNA clone is associated with increased risk for Alzheimer's disease

Mitochondrial DNA variants observed in Alzheimer disease and Parkinson disease patients

free radicals, and neurodegeneration

Impairment in mitochondrial cytochrome oxidase gene expression in Alzheimer's disease

Functional alterations in Alzheimer's disease: Selective loss of mitochondrial-encoded cytochrome oxidase mRNA in the hyppocampal formation

Lipoic acid and N-acetyl-cysteine decrease mitochondrial-related oxidative stress in Alzheimer disease patient fibroblasts

Controlled trial of N-acetylcysteine for patients with probable Alzheimer's disease

Inhibition of acrolein-induced apoptosis by the antioxidant N-acetylcysteine

Efficacy of a vitamin/nutriceutical formulation for moderate-stage to later-stage Alzheimer's disease: A placebo-controlled pilot study

Co-administration of N-acetylcysteine, vitamin B12 and folate in cognitively impaired hyperhomocysteinaemic patients

Does N-acetylcysteine modulate post-translational modifications of transthyretin in hemodialysis patients?

Mechanisms of transthyretin inhibition of β-amyloid aggregation in vitro

Transthyretin: The servant of many masters

Up-regulation of β-amyloidogenesis in neuron-like human cells by both 24-and 27-hydroxycholesterol: Protective effect of N-acetyl-cysteine

α-synuclein aggregates induce c-Abl activation and dopaminergic neuronal loss by a feed-forward redox stress mechanism

N-Acetyl-cysteine may support dopamine neurons in Parkinson's disease: Preliminary clinical and cell line data

N-acetyl-cysteine is associated with dopaminergic improvement in Parkinson's disease

Oxidative modification of peroxiredoxin is associated with drug-induced apoptotic signaling in experimental models of Parkinson disease

Glutamate uptake

Interaction of L-cysteine with a human excitatory amino acid transporter

Cysteine transport through excitatory amino acid transporter 3 (EAAT3)

N-acetylcysteine reverses mitochondrial dysfunctions and behavioral abnormalities in 3-nitropropionic acid-induced Huntington's disease

Effect of exogenous and endogenous antioxidants on 3-nitropropionic acid-induced in vivo oxidative stress and striatal lesions: Insights into Huntington's disease

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease

Mitochondrial dysfunction due to mutant copper/zinc superoxide dismutase associated with amyotrophic lateral sclerosis is reversed by N-acetylcysteine

N-acetyl-L-cysteine improves survival and preserves motor performance in an animal model of familial amyotrophic lateral sclerosis

Randomized, double-blind, controlled trial of acetylcysteine in amyotrophic lateral sclerosis

N-acetylcysteine, a glutamate modulator, in the treatment of trichotillomania: A double-blind, placebo-controlled study

Overview on the effects of N-acetylcysteine in neurodegenerative diseases

Plasma glutathione levels decreased with cognitive decline among people with mild cognitive impairment (MCI): A two-year prospective study

Cys34-cysteinylated human serum albumin is a sensitive plasma marker in oxidative stress-related chronic diseases

Serum albumin cysteine trioxidation is a potential oxidative stress biomarker of type 2 diabetes mellitus

Thiol disulfide exchange reactions in human serum albumin: The apparent paradox of the redox transitions of Cys34

APOE and MAPT are associated with dementia in neuropathologically confirmed Parkinson's disease

Disulfide bond formation in microtubule-associated tau protein promotes tau accumulation and toxicity in vivo

N-acetylcysteine prevents amyloid-β secretion in neurons derived from human pluripotent stem cells with trisomy 21

Funding: This research received no external funding.

The author declares no conflict of interest.