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Oxidative Stress and Redox Enzymes in Neurodegenerative Diseases: History
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Subjects: Biochemistry & Molecular Biology
Contributor: Dong-Hoon Hyun , Jaewang Lee

Neurodegenerative diseases comprise a wide range of diseases with heterogeneous aetiologies and exhibit degenerative processes commonly accompanied by oxidative stress and mitochondrial dysfunction. Mitochondrial dysfunction is a major risk factor associated with aging and the initiation and progression of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Neurodegenerative diseases are characterised by irreversible, progressive loss of neuronal cells, formation of protein aggregates, and a decline in cognitive or motor functions. Neurodegenerative diseases are induced by imbalanced redox homeostasis and impaired energy metabolism, as hypothesised by several aging theories, including the free radical theory, the mitochondrial dysfunction theory, the genetic theory, and the telomere shortening theory.

  • neurodegenerative diseases
  • oxidative stress

1. Introduction

Neurodegenerative diseases comprise a wide range of diseases with heterogeneous aetiologies and exhibit degenerative processes commonly accompanied by oxidative stress and mitochondrial dysfunction [1]. Mitochondrial dysfunction is a major risk factor associated with aging and the initiation and progression of neurodegenerative diseases, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Neurodegenerative diseases are characterised by irreversible, progressive loss of neuronal cells, formation of protein aggregates, and a decline in cognitive or motor functions [2]. Neurodegenerative diseases are induced by imbalanced redox homeostasis and impaired energy metabolism [3], as hypothesised by several aging theories, including the free radical theory [4], the mitochondrial dysfunction theory [5], the genetic theory [6], and the telomere shortening theory [7].
The brain has a high demand for molecular oxygen and consumes about 20% of inhaled oxygen to maintain its function. More than 50% of the ATP produced in the brain is used to restore the resting membrane potential coupled to the Na+/K+ ATPase pump [8]. The brain contains large amounts of transition metals (e.g., copper and iron), which are responsible for the production of reactive oxygen species (ROS) [3]. In addition, brain cell membranes are enriched with polyunsaturated fatty acids, which are prone to lipid peroxidation. However, levels of antioxidant enzymes/molecules are relatively lower than in other organs. As a result, the brain is more sensitive to oxidative stress than any other part of the body.
The brain uses around 20% of the body’s glucose-derived energy and relies heavily on mitochondrial ATP production [9]. Therefore, normal brain mitochondrial function is required to maintain crucial physiological processes, such as synaptic transmission. Because deficits in mitochondrial function have been identified in many neurodegenerative diseases, maintenance of normal mitochondrial function during aging can be a way to prevent the progression of neurodegenerative diseases. In addition, the inflammatory process is identified to be closely associated with multiple pathways of neurodegenerative diseases. Inflammatory responses in the peripheral system can lead to consequent neuroinflammation and neurodegeneration [10]. 

2. Oxidative Stress and Redox Enzymes in Neurodegenerative Diseases

2.1. Alzheimer’s Disease

AD is the most common neurodegenerative disease affecting the elderly population and is characterised by selective, progressive death of cholinergic neurones, leading to the loss of cognitive functions and behavioural impairment. AD is an age-related disease, but can also be found in some young populations. The pathology of AD includes two types of protein aggregates, extracellular senile plaques containing amyloid β (Aβ) and intracellular neurofibrillary tangles formed from hyperphosphorylated tau [11][12]. Along with tau, the accumulation of oligomerised Aβ peptides mediates inflammation in neuronal cells, causing neurodegeneration. These protein aggregates induce deterioration in synaptic transmission, cholinergic denervation, and depleted acetylcholine.
Transition metals, such as iron, zinc, and copper, are known to produce ROS in cells. Aβ interacts with transition metals and is responsible for normal cellular signalling. However, Aβ can be aggregated through complexing with redox active copper [13]. Tau also is aggregated and phosphorylated after binding to zinc and iron [14]. High zinc levels in the neocortex and hippocampus in AD patients show the key role of zinc in redox homeostasis in the affected brain areas [15][16]. Recently, the putative role of iron in AD has been examined. Treatment with iron chelator improves cognitive capability, reducing Aβ aggregation and tau hyperphosphorylation in AD mouse model [17][18]. However, there remains a dilemma about the use of iron chelators because of iron’s significance in energy metabolism. Iron-sulphur clusters are essential factors for electron transfer in mitochondrial respiratory complex I, II, and III [19][20][21]. The Fenton reaction raises cellular ROS levels in the condition of high iron, whereas the low levels of iron decrease mitochondrial activity [22][23]. A recent study shows that lipid peroxidation promoted by the Fenton reaction leads to a new type of cell death, called ferroptosis [24]. AD post-mortem studies demonstrate typical features of ferroptotic cell death, including the increase of 4-HNE and the decrease of glutathione [25][26][27]. Inflammation in response to the formation of Aβ aggregates disrupts zinc homeostasis, leading to the release of zinc from the cerebrum and increased oxidative stress [28]. Although diverse functions of zinc make researching the mechanism between zinc and AD difficult, a recent study mentions that the supplement of zinc can reduce AD progression by lowering NLRP3-dependent inflammation [29]. As considered by an aforementioned study, low zinc may increase Aβ level in the brain of transgenic mice harbouring amyloid precursor protein with Swedish mutation and mutant human presenilin 1 (APPSwe/PS1ΔE9) [30].
ROS and oxidative stress play a crucial role in AD, as identified by oxidative stress induced by Aβ and oxidative damage, such as DNA/RNA oxidation (e.g., 8-hydroxydeoxyguanosine, 8-hydroxyganosine), protein oxidation (e.g., carbonylated proteins), and lipid peroxidation (e.g., 4-hydroxynoneal, malondialdehyde) [31][32][33]. Oxidative stress induced by accumulated Aβ inhibits complex IV activity, resulting in mitochondrial dysfunction and ATP depletion [31][32][33].
In addition, levels of antioxidants and antioxidant enzymes are decreased in AD models and patients with AD, suggesting an altered equilibrium between ROS production and antioxidant capacity. Vitamins C and E are decreased in the plasma of patients with mild cognitive impairment (MCI) or mild AD and in the cerebral spinal fluid of AD patients [34][35]. Glutathione (GSH) levels are also decreased in MCI and AD brains [36][37]. Glutathione S-transferase (GST), involved in GSH metabolism, is found in a modified carbonylated form in aged dog brains and C. elegans expressing Aβ [38][39] and in a nitrated form in MCI brains [40]. In particular, levels of superoxide dismutase (SOD), glutathione peroxidase, and catalase are decreased in the cortex of AD patients, whereas SOD levels (not activity) are increased in the hippocampus and amygdala [37]. Peroxiredoxins (Prxs), which remove hydrogen peroxide, are also affected by oxidative/nitrative stress. Prx2 oxidation is caused by Aβ in SAMP8 mice, while Prx2 level is increased in AD brains from SAMP8 mice and human [41][42]. Moreover, Prx6 is oxidatively modified in MCI brains [40].
At present, three choline esterase inhibitors (donepezil, rivastigmine, and galantamine) and one N-methyl-D-aspartate antagonist (memantine) approved by the Food and Drug Administration (FDA) have been used to treat AD in association with a Ginkgo biloba extract (EGb761, antioxidant) [43][44]. However, there is no known cure for AD. These drugs can delay AD progression, but induce common side-effects, including nausea, vomiting, and diarrhoea.

2.2. Parkinson’s Disease

PD is the second most common neurodegenerative diseases (ND) after AD in aged people. PD is characterised by the irreversible death of dopaminergic neurones in the substantia nigra (SN), causing postural instability, tremor, rigidity, and bradykinesia. The hallmark of PD is protein aggregates called Lewy bodies (LB) containing α-synuclein [45]. Mitochondrial dysfunction was explained first in PD pathogenesis as inhibition of mitochondrial complex I by 1-methyl-4-phenylpyridinium (MPP+), which is a metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), causing parkinsonism [46]. Other toxic molecules, such as paraquat and 6-hydroxydopamine, can cause the symptoms of PD [47][48]. Oxidative stress and ROS are responsible for the pathogenesis of sporadic forms of PD. A high level of Fe2+ in the SN of PD patients promotes lipid peroxidation through the Fenton reaction, leading to nigral cell death [49]. Other transition metals (e.g., copper, zinc, and manganese) can cause neurodegeneration [50][51][52]. In addition, nitric oxide (NO) produced by neuronal nitric oxide synthase (nNOS) or inducible NOS (iNOS) inhibits mitochondrial complexes I and IV, resulting in enhanced production of ROS [53][54], consistent with enhanced levels of nNOS and iNOS in basal ganglia of post-mortem PD brains [55][56]. Deletions in mitochondrial DNA (mtDNA) have been found in the SN of elderly people and PD patients [57]. NO can induce lipid peroxidation by forming S-nitrosothiol compounds, resulting in PD phenotypes in mice treated with maneb and paraquat [58].
Familial cases of PD can be caused by various mutations in a number of genes, including α-synuclein, parkin, PTEN-induced kinase 1 (PINK1), DJ-1, and leucine-rich repeat kinase 2 (LRRK2) [59]. Both wild-type and mutant forms of α-synuclein aggregate during the progression of PD and are enriched in LB [60]. MPTP-treated transgenic mice exhibit overexpressed α-synuclein and dysfunctional mitochondria, resulting in nigral cell death [61]. Mutated parkin and PINK1 are related to the accumulation of dysfunctional mitochondria through reduced clearance of impaired mitochondria [62][63]. DJ-1 is a protein deglycase, prohibiting the aggregation of α-synuclein by functioning as a chaperone and an oxidative stress sensor [64][65]. DJ-1 protects neuronal cells against excessive oxidative stress. Mutations in DJ-1 are associated with autosomal recessive parkinsonism through multiple functions, such as an oxidative stress sensor and redox chaperone [66][67]. Mutated forms of LRRK2 increase cell sensitivity to mitochondrial inhibitors [68]. Therefore, the close relationships between oxidative stress, mitochondrial dysfunction, and accumulation of protein aggregates are key to PD pathogenesis.
At present, L-dopa (a natural precursor of dopamine) has been used with carbidopa, which blocks the conversion of L-dopa to dopamine outside the brain [69][70]. Safinamide, a monoamine oxidase B inhibitor, is used for patients with idiopathic PD [71]. In addition, antioxidants targeting the mitochondria can be effective for PD. Mitoquinone (MitoQ), which is ubiquinone conjugated to triphenylphosphonium (TPP), scavenges peroxyl, peroxynitrites, and superoxide radicals [72] and improves mitochondrial membrane potential (MMP) [73]. These drugs can improve PD symptoms but induce side effects such as fatigue and dizziness.

2.3. Amyotrophic Lateral Sclerosis

ALS, also called Lou Gehrig’s disease, is the most common type of motor neurone disease and is characterised by a progressive loss of motor neurones in the spinal cord, cortex, and brainstem. Oxidative stress, excitotoxicity, and inflammation are believed to be involved in ALS, although the links between them are not clear. A different type of protein aggregate (called Bunina bodies) also has been identified in ALS [74]. Mitochondrial dysfunction is an initiator of ALS. Mutations in Cu/Zn superoxide dismutase (SOD1) affect its antioxidant activity and cause accumulation of H2O2 and hydroxyl radicals, leading to the generation of impaired mtDNA and misfolded proteins [75]. Mutant SOD1 localises into the mitochondria and interacts with voltage-dependent anion-selective channel 1 (VDAC1), resulting in blockage of the exchange of ions and proteins between the mitochondria and cytosol [76]. Oxidative damage markers of DNA oxidation (e.g., 8-OHdG) and lipid peroxidation (e.g., isoprostane) have been identified in the brain of ALS patients [77]. ROS also cause mtDNA mutations, membrane permeability change, and impaired calcium homeostasis, leading to ALS [78][79].
Recently, two ALS drugs, riluzole (a glutamatergic neurotransmission inhibitor) and edaravone (an antioxidant drug), have been approved by the FDA [80].

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