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Oxidative Stress in Amyotrophic Lateral Sclerosis: History
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Contributor: Anca Motataianu , Georgiana Serban , Laura Barcutean , Rodica Balasa

Amyotrophic lateral sclerosis (ALS) is a grievous neurodegenerative disease whose survival is limited to only a few years. In spite of intensive research to discover the underlying mechanisms, the results are fairly inconclusive. Multiple hypotheses have been regarded, including genetic, molecular, and cellular processes. Notably, oxidative stress has been demonstrated to play a crucial role in ALS pathogenesis. In addition to already recognized and exhaustively studied genetic mutations involved in oxidative stress production, exposure to various environmental factors (e.g., electromagnetic fields, solvents, pesticides, heavy metals) has been suggested to enhance oxidative damage. 

  • amyotrophic lateral sclerosis
  • oxidative stress
  • genetic factors
  • environmental factors
  • neurodegeneration

1. Introduction

Amyotrophic lateral sclerosis (ALS) etiology is not yet completely understood despite extensive research. Roughly 10% of ALS cases belong to a familial, mainly autosomal dominant inheritance pattern, while the remaining 90% are sporadic forms with no apparent genetic basis [1]. Numerous external occupational and environmental factors have been associated with ALS, including exposure to different chemicals, metals, and pesticides, electromagnetic fields (EMFs), and lifestyle choices, such as smoking and excessive physical exercise [2]. Nevertheless, these factors do not directly cause ALS but act upon various internal susceptibility factors and lead to ALS development. Over 30 mutations have been found to correlate with ALS, particularly its familial form, in genes, such as superoxide dismutase 1 (SOD1), transactive response (TAR)-DNA binding protein (TARDBP, previously called TDP43), angiogenin (ANG), fused in sarcoma RNA binding protein (FUS), and chromosome 9 open reading frame 72 (C9orf72) [3][4]. ALS is a multifactorial disease caused by various defective cellular and molecular processes, including glutamatergic excitotoxicity, axonal transport, RNA and protein metabolism, mitochondrial dysfunction, and oxidative stress (OS) [3][5][6].
Mitochondria are organelles of great importance in the human body due to their role in converting stored energy into adenosine triphosphate (ATP) via oxidative phosphorylation and phospholipid biogenesis, calcium buffering and regulating programmed cell death [1]. Oxidative phosphorylation is the primary source of free radicals, such as reactive oxygen (ROS), nitrogen (RNS), and sulphur (RSS) species, which are found in all cells but in limited amounts due to the counteracting antioxidant mechanisms [7].

2. OS and Mitochondrial Dysfunction in ALS

OS arises due to disequilibrium caused by excessive ROS production and insufficient compensatory antioxidant systems. The oxygen-free radicals are oxygen species produced by incomplete oxygen reduction in different enzymatic and non-enzymatic cellular processes [8][9]. Mitochondria are the OS mechanism’s primary target and the largest ROS producer [10].
Mitochondria are the primary source of ROS due to their role in ATP production via oxidative phosphorylation, whose significant adverse effect is the production of unpaired electrons [11]. The electron transport chain comprises five multiprotein complexes that mediate the interaction between these electrons and oxygen, creating ROS such as hydrogen peroxide (H2O2), superoxide anions (O2−), and hydroxyl radicals (HO−) [9][12]. Mitochondrial complex I (reduced nicotinamide adenine dinucleotide [NADH] coenzyme Q reductase) catalyses the electron transfer from NADH to ubiquinone (coenzyme Q). Ubiquinone also receives electrons from complex II (succinate dehydrogenase). The reduced ubiquinone donates its electrons to complex III (cytochrome bc1) and, eventually, to cytochrome c (cytC). Complex IV (cytC oxidase) participates in the interaction between molecular oxygen and the electrons removed from cytC, leading to water formation [1]. Complexes I, II, and III are the most frequently associated with premature electron leakage to oxygen and play a significant role in ROS production [13].
In addition, increased ROS levels lead to the formation of other reactive species, such as RNS, due to O2− interacting with other molecules, such as nitric oxide, to form peroxynitrite (ONOOˉ). Moreover, in addition to ROS and RNS, mitochondria produce RSS, which are also incredibly reactive. Free oxygen radicals progressively damage proteins, lipids, and nucleic acids, resulting in inefficient cellular processes, inflammation, and cell death [1][3]. Mitochondrial internal components and mitochondrial DNA (mtDNA), in particular, are highly susceptible to OS-induced damage, eventually hindering normal mitochondrial bioenergetics, increasing ROS production and OS [14]. The protective antioxidant systems comprise both enzymatic and non-enzymatic processes. The key enzymes involved in catalytic ROS removal are superoxide dismutases (SODs), catalase (CAT), glutathione peroxidases (GPXs), glutathione reductase (GR), and thioredoxin (TRX). In addition, the non-enzymatic complexes primarily comprise vitamins A, C, and E, glutathione (GSH), and proteins such as albumin and ceruloplasmin [9][15].
Abnormally high free radical levels and low antioxidant systems represent a universally accepted yet incompletely understood pathological ALS characteristic. OS unquestionably plays a crucial role in motor neuron death, but the precise timing of oxidative damage remains unknown [16]. OS biomarkers have been identified in ALS patients’ brain tissue, cerebrospinal fluid (CSF), blood, and urine [17]. Because the life expectancy of ALS patients is relatively short, it is impossible to monitor OS biomarkers over an extended period. Moreover, it is challenging to determine whether OS is a cause of ALS-associated neurodegeneration or a consequence of other underlying etiologic factors because of its sporadic o nset and the current lack of methods to predict ALS development [8]. Studies with a murine ALS model have found modified mitochondrial structures and nuclear factor erythroid 2-related factor 2 (Nrf2) pathway activation, which generally occurs due to OS-induced damage and stimulates the formation of intracellular antioxidant molecules, during early ALS stages, implying OS involvement in the initial phase of ALS [18][19].
However, these studies used the murine mutant SOD1 ALS model, and SOD1 mutations only account for 20% of human familial ALS cases. Babu et al. [20] found a significant increase in lipid peroxidation and decreases in antioxidant enzymes CAT, GR, GSH, and glucose-6-phosphate dehydrogenase (G6PD) in the erythrocytes of 20 sporadic ALS patients. The changes progressed alongside ALS pathogenesis, consistent with OS involvement in ALS development. Furthermore, the abovementioned environmental and occupational risk factors mutually stimulate and induce pro-oxidative states, which can eventually adversely affect motor neurons [21].
Coiled-coil-helix-coiled-coil-helix domain-containing protein 10 (CHCHD10) is a mitochondrial protein located in the intermembrane space (IMS) with no recognised function [22]. However, it is believed to be involved in maintaining mitochondrial cristae morphology and proper oxidative phosphorylation. Overexpression of mutant CHCHD10 containing an allele associated with ALS leads to altered mitochondrial structure and defective electron transport chain activity, particularly in multiprotein complexes I, II, III, and IV [23][24]. Moreover, fibroblasts had mitochondrial ultrastructural damage and mitochondrial network fragmentation in an ALS patient carrying a CHCHD10 mutation [23].

3. Genetic Variants and OS

3.1. SOD1 Mutations

SOD1 is located on chromosome 21 and encodes an important intracellular antioxidant enzyme. SOD1 is found mainly in the cytosol, with approximately 5% of total cellular SOD1 found in the mitochondrial IMS. It primarily converts the O2− into H2O2, which is then converted to water and oxygen by other antioxidant enzymes, such as CAT, GPXs, and peroxiredoxin [25]. An alternative process for removing primary ROS is detoxification by cytC, the main advantage of which is the absence of secondary ROS. However, its major drawback is its interaction with H2O2 resulting from SOD1 activity (cytochrome peroxidation), leading to a highly reactive molecule, oxoferryl-cytC [25].
To adequately fulfil its function, SOD1 must reach a mature, highly stable form via complex post-translational modifications (PTMs) facilitated by a copper chaperone for SOD1 (CCS) [26]. PTMs include zinc and copper metal binding, disulphide bond formation and folding, and exposure of hydrophobic regions for further dimerisation [1]. Cytosolic SOD1 can traverse the outer mitochondrial membrane (OMM) through the translocase of outer membrane (TOM). Its return is prevented by CCS-mediated establishing disulphide bonds and inserting metal ions [1]. CCS distribution influences SOD1 localisation. Cytosolic CCS impedes SOD1 mitochondrial import, while mitochondrial CCS prevents SOD1 cytosolic export. Moreover, it acts as an oxygen sensor. Hyperoxia maintains cytosolic CCS, while hypoxia promotes the mitochondrial import of CCS and SOD1 [26]. Therefore, increased mitochondrial respiratory chain activity, CCS intra-mitochondrial translocation, and SOD1 maturation under hypoxia act as a compensatory antioxidant system [3]. In addition, the Mia40/Erv1 pathway participates in CCS mitochondrial import in a respiratory chain-dependent manner [26].
SOD1 has been implicated in ALS pathogenesis, with more than 160 mutations so far identified that typically change only a single amino acid. However, the exact mechanism leading to motor neuron death remains to be determined. While SOD1 mutations are primarily found in familial ALS cases, they likely also contribute to sporadic ALS [27]. Notably, mitochondrial accumulation of mutant SOD1 protein is characterised by increased enzymatic function, which appears to cause neurodegeneration [21][27][28][29]. However, the precise mechanisms of SOD1 toxicity are not fully understood. Nevertheless, several hypotheses have been proposed. SOD1 has a low level of intrinsic peroxidase activity, which can be amplified by high ROS levels [30]. SOD1 containing the Av5, H48Q, and G93A mutations has enhanced peroxidase activity and catalyses H2O2 conversion to HOˉ, irreversibly inactivating the dismutase structure [30]. Furthermore, O2− shows a higher propensity for nitric oxide than mutant SOD1, leading to ONOOˉ production with further tyrosine nitration of cellular proteins, resulting in neuronal death [8][31]. SOD1 maturation is a complex process and is highly susceptible to disruption. Numerous amino acid mutations affecting metal binding or disulphide bridge formation lead to misfolded proteins, each of whose structure is unstable and inclined to create insoluble SOD1 aggregates. However, mutant SOD1 cannot adequately respond to CCS-induced PTMs, eluding the maturation process essential for normal function and enhancing intracellular ROS accumulation [32]. A negative feedback cycle occurs in which OS and mitochondrial damage caused by misfolded SOD1 lead to further SOD1 misfolding and further mitochondrial damage [1]. However, mutant SOD1 aggregates interact with OMM proteins involved in mitochondrial apoptosis, such as Bcl12 and voltage-dependent anion channel (VDAC), activating pro-apoptotic pathways. Regardless of the mechanisms involved, motor neuron death results [3][33] (Figure 1).
Figure 1. Genetic risk factors involved in oxidative stress in ALS patients. (SOD: superoxide dismutase; ROS: reactive oxygen species; DPR: dipeptide repeat proteins).

3.2. TARDBP Mutation

TARDBP, also known as TDP-43, is located on chromosome 1 and encodes a ubiquitous heterogeneous nuclear ribonucleoprotein comprising four domains: two RNA highly conserved recognition motifs essential for its role in protein biogenesis, a C-terminal glycine-enriched low complexity domain (LCD) involved in protein-protein interactions, and an N-terminal region whose function remains contentious [34][35]. It has various functions, particularly in RNA transcription, maturation, transport and translation, and plays a crucial role in intracellular stress management. TARDBP participates in the biogenesis and maintenance of stress granules, small membrane-less structures that form due to cellular exposure to stress and protect RNA and its associated ribonucleoproteins [36]. Moreover, TARDBP interacts with numerous proteins involved in diverse physiological processes, such as RNA metabolism, the immune response, and stress-induced pathways [37].
Almost 10% of ALS familial cases are associated with TARDBP mutations, which mostly affect its LCD. The key properties of mutated TARDBP include an increased tendency to aggregate, cytoplasmic mislocalisation, unstable structure, protease resistance, and altered protein-protein interactions [38][39]. Furthermore, patients with sporadic ALS frequently have elevated TARDBP levels within neuronal and cytoplasmic inclusions, a current hallmark of ALS pathogenesis [39]. Altered cellular redox balance has also been suggested as a causal factor in ALS pathogenesis. Several studies have demonstrated a reciprocal relationship between OS and TARDBP mutations: whereas TDP-43 mutations impair mitochondria, OS production greatly increases TDP-43 toxicity [40][41]. On the one hand, Cohen et al. [42] showed that OS induces cysteine disulphide cross-linking in TARDBP, decreasing protein solubility and enhancing the formation of insoluble cytoplasmic aggregates. More recently, OS was found to promote the acetylation of lysine-145, particularly in cytoplasmic TARDBP, leading to its aggregation, LCD hyperphosphorylation, and loss of normal TARDBP function [43]. On the other hand, Magrane et al. [44] have shown that mutated TARDBP (A315T) overexpression impairs mitochondrial structure and transport. Conversely, Wang [45] showed that both wildtype and mutated TARDBP (Q331K and M337V) reduced mitochondrial density in neuritis and mitochondrial dynamics. Altered mitochondrial function can enhance TARDBP aggregation through reduced GSH levels, leading to unbalanced ROS overproduction and neurodegeneration. Moreover, several studies have found that mutated TARDBP markedly decreased the antioxidant expression of Nrf2, further enhancing OS [42][43][46][47] (Figure 1).

3.3. FUS Mutation

FUS is located on chromosome 16 and encodes a member of the RNA/DNA-binding protein family that comprises two main domains: an N-terminal LCD region involved in transcriptional activation and a C-terminal region implicated in RNA and protein binding [48]. Similar to TARDBP, most mutations occur within the last 12 amino acids of the C-terminal region, particularly in familial ALS forms. However, N-terminal domain mutations are often associated with sporadic ALS [49]. Patients with FUS mutations typically develop juvenile ALS, with onset before the age of 40 years [48]. Due to its nucleic acid binding capacity, FUS is implicated in RNA metabolism and DNA repair [50].
FUS and TARDBP share similar molecular mechanisms that lead to ALS occurrence, both involving the cytosolic accumulation of protein aggregates that are a hallmark of ALS [49]. Nevertheless, FUS has been found to cause ALS by a DNA-related process. Due to their high metabolic demands, neurons are characterised by intense energy production, with a detrimental elevation in ROS, which is harmful to DNA. Wang et al. [50] showed that FUS mutants, particularly R521H and P525L, failed to mend OS-induced DNA damage properly. Consequently, significant numbers of unrepaired DNA strand breaks accumulate in the neurons, eventually leading to motor neuron death (Figure 1).

4. Environmental Factors Associated with OS in ALS

Already recognised and exhaustively studied mutations can no longer thoroughly explain ALS pathogenesis. Exposure to various environmental factors, such as EMFs, solvents, heavy metals, and agricultural pesticides, has been hypothesised to contribute to ALS pathogenesis. Nevertheless, the contribution of several occupational factors to ALS has proven difficult to assess since there are no clear signs indicative of ALS development in ostensibly healthy individuals. Therefore, exposure to various environmental factors is based solely on patient recollection, and existing studies have provided controversial evidence that has not clarified the role of environmental factors in ALS (Figure 2).
Figure 2. Environmental risk factors involved in oxidative stress in ALS patients. (ROS: reactive oxygen species; Hg: mercury; Pb: lead; Cd: cadmium; Cr: chromium; Se: selenium; Fe: iron; Mn: manganese; Ni: nickel).

4.1. EMFs

EMFs occur naturally and are ever present in people’s lives. However, environmental exposure has increased lately due to the rapid development of artificial EMF sources [51]. There are generally two EMF types: low frequency (LF-EMF) from power lines, household electrical appliances, and computers, and high frequency (HF-EMF) from radars, radios, mobile phones, and television broadcast towers [51]. Most studies have focused on the LF-EMF but provide conflicting results regarding LF-EMF-induced neurodegeneration. A Swedish meta-analysis found a potential positive association between LF-EMF exposure and ALS occurrence. However, they could not discriminate between isolated and occupational LF-EMF exposure [52]. An updated study by the same group found that LF-EMF occupational exposure carries an absolute risk for ALS [53]. A prospective study that followed patients for 17.3 years found a positive exposure-dependant association between occupational exposure to shallow frequency magnetic fields and ALS mortality [54]. An Italian study further supports these findings, confirming the predisposing effect of the proximity to overhead power lines on increasing ALS risk [55]. However, a Dutch study found no elevated risk of ALS development in people living near LF-EMF sources [56]. Therefore, these studies should be interpreted cautiously, as their correlations are based broadly on registry data, which is much more susceptible to bias [57][58]. Evidence for HF-EMFs is limited. Luna et al. [51] performed an epidemiological study that hypothesised a potential association between HF-EMF exposure from mobile communication antennas and ALS occurrence. However, further studies are needed to confirm or refute these findings.
The pathological implications of EMF exposure on the nervous system remain under investigation. Various neurological effects have been reported, such as disturbances in circadian rhythm, altered cognitive function, abnormal neuronal electrical activity, modified neurotransmitters release (e.g., glutamate-mediated excitotoxicity), elevated ROS production, and impaired blood-brain barrier permeability [51][59]. Both in vivo and in vitro studies have found that EMF-induced OS significantly influences different cellular processes, including gene dysregulation, abnormal protein aggregation, and neuroinflammation, which all have established roles in ALS [57][58][59][60]. Several studies have reported a substantial deterioration in antioxidant defence mechanisms in aged rats exposed to LF-EMF [61][62][63]. Moreover, exposure to high LF-EMF leads to neurological effects consequent not only to lipid peroxidation, but also to disturbances in several molecular processes, such as iron-related gene dysregulation in SOD1 mouse mutant models [63][64]. Other murine studies on mutant SOD1 have found no apparent EMF effect on ALS onset and survival. However, motor performances appeared worse after exposure compared to unexposed controls [61][65].

4.2. Solvents

Solvents are increasingly present in modern society due to their inclusion in different industrial and household products, such as paints, adhesives, and cleaning solutions. They can penetrate the blood-brain barrier through their lipophilic properties and cause various neurological disturbances, from cognitive impairment to motor deficits. Moreover, solvents accumulate within fatty tissues with recurrent exposure and continue to damage nerve function [66][67]. While solvents have gained increasing recognition as ALS inducers, findings on the relationship between solvent exposure and ALS pathogenesis have been contradictory. Koeman et al. [54] disproved any potential connection between ALS and aromatic and chlorinated solvents. However, a Swedish case-control study [68] found an inverse association between methylene chloride exposure, a common solvent with known carcinogenic effects in humans, and ALS risk in people younger than 65, contrasting with a previous study [69] that found no connection between them. Formaldehyde exposure, particularly among healthcare workers, has provided conflicting results. Some studies support its role in increasing ALS risk, particularly in males [68][70][71], while another study found little or no association [69]. However, a positive association between aromatic solvents and ALS was reported by Malek et al. [72]. Moreover, Andrew et al. [73] concluded that higher solvent exposure increased ALS risk in industrial employees, consistent with the findings of Malek et al. in a residential setting [74].
Volatile organic compounds (VOCs), particularly toluene and xylene, are most frequently implicated in impairing central nervous system (CNS) function. Their primary pathological mechanism is OS due to GSH depletion [66][75]. Studies have shown that GSH levels decrease as ALS progresses, supporting the hypothesis that VOC exposure might contribute to inducing latent ALS [66][76][77][78]. Organic solvents also deplete mitochondrial ATP, leading to abnormal functioning of ATP-dependent cellular processes and eventually apoptosis [66][79]. Constant VOC exposure is associated with increased neuronal excitation. Given the already recognised involvement of motor neuron hyperexcitability in ALS pathogenesis, the latter mechanism supports the potential role of VOCs in ALS progression [66][80]. Furthermore, toluene exposure has been shown to intervene in axonal transport by reducing levels of microtubule-associated protein 2 (MAP2), leading to the loss of anterior horn neurons in ALS patients [66][81][82][83].

This entry is adapted from the peer-reviewed paper 10.3390/ijms23169339

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