CNS Redox Homeostasis And Dysfunction in Neurodegenerative Diseases Part 1

Abstract: 

A single paragraph of about 200 words maximum: neurodegenerative diseases (ND), such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, pose a global challenge in the aging population due to the lack of treatments for their cure. 

Amyotrophic lateral sclerosis (ALS) is a disease that affects the nervous system and can cause problems such as muscle weakness, atrophy, swallowing, and breathing difficulties. Although ALS is often confused with diseases that cause loss of memory and cognitive abilities, ALS does not affect brain function.

Nevertheless, ALS may have some psychological effects on patients, including the possibility of mild problems with memory and cognition, such as difficulty concentrating and fatigue. However, these problems are usually limited to mild symptoms and do not affect the patient's daily life or most activities that can be participated in.

Having ALS does not mean that there will be problems with memory. On the contrary, a positive attitude is constructive for the patient's recovery and restoration of physical function. Therefore, when dealing with ALS, patients need to maintain an optimistic and cheerful attitude and improve their physical function through active exercise and appropriate rehabilitation treatment.

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In short, there is no direct connection between ALS and memory, but patients need to maintain a good mentality and a positive attitude, which is essential for physical recovery and rehabilitation. It can be seen that we need to improve memory, and Cistanche can significantly improve memory because it has antioxidant, anti-inflammatory, and anti-aging effects, which can help reduce oxidation and inflammatory reactions in the brain, thereby protecting the health of the nervous system. In addition, Cistanche can also promote the growth and repair of nerve cells, thereby enhancing the connectivity and function of neural networks. These effects can help improve memory, learning ability, and thinking speed, and can also prevent the occurrence of cognitive dysfunction and neurodegenerative diseases.

Despite various disease-specific clinical symptoms, ND has some fundamental common pathological mechanisms involving oxidative stress and neuroinflammation. 

The present review focuses on the major causes of the central nervous system (CNS) redox homeostasis imbalance comprising mitochondrial dysfunction and endoplasmic reticulum (ER) stress. 

Mitochondrial disturbances, leading to reduced mitochondrial function and elevated reactive oxygen species (ROS) production, are thought to be a major contributor to the pathogenesis of ND. ER dysfunction has been implicated in ND in which protein misfolding causes ER stress. The consequences of ER stress range from an increase in ROS production to altered calcium efflux and proinflammatory signaling in glial cells. 

Both pathological pathways have links to necroptotic cell death, which has been implicated in playing an important role in ND. Pharmacological targeting of these pathological pathways may help alleviate or slow down neurodegeneration.

Keywords: mitochondria; reactive oxygen species (ROS); endoplasmic reticulum (ER) stress; unfolded protein response (UPR); neuroinflammation; ferroptosis; Alzheimer's disease; Parkinson's disease; amyotrophic lateral sclerosis.

1. Introduction

Redox homeostasis is acknowledged to play a major role in both normal cellular function and disease of the human central nervous system (CNS). 

This review aims to cover several major intracellular pathways affecting redox homeostasis and being relevant in the scope of degenerative diseases of the CNS. Here, we reveal several important linking axes between the pathways of mitochondrial reactive oxygen species (ROS) production and ferroptosis, and oxidative protein refolding in endoplasmic reticulum (ER) and neuroinflammation. 

Finally, we discuss the relevance of these pathways in the pathogenesis of several NDs, particularly Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease.

2. Redox Homeostasis in Mitochondria and Production of ROS

Mitochondria-dependent aerobic metabolism has a clear advantage for the production of energy-carrying substrates such as (adenosine 50 -triphosphate) ATP and maintaining body temperature or metabolite homeostasis. 

On the other hand, mitochondria also take the central position in the intracellular production of reactive oxygen species (ROS) [1]. Mitochondrial ROS generation is initiated upon electron escape from the electron transport chain (ETC) and the reaction of this electron directly with oxygen, resulting in one-electron reduction and the formation of superoxide anion radical O2 − (Figure 1a). 

The consecutive reduction of superoxide gives rise to oxygen radical species and hydrogen peroxide, which is freely diffusible and relatively stable. The physiological superoxide detoxification mechanism is based on a dismutation reaction, which yields hydrogen peroxide and water molecules. This reaction is catalyzed by superoxide dismutase (SOD) including cytosolic SOD1 and mitochondrial matrix SOD2. 

Hydrogen peroxide, in turn, is reduced by several enzymes comprising glutathione peroxidases (GPX), peroxiredoxins, and catalase. Even though primarily located in the cytosol, a fraction of SOD1 translocates to the mitochondrial intermembrane space (IMS). The role of SOD1 in this compartment is under debate because IMS contains a high concentration of cytochrome C, which acts as an electron carrier in the ETC [2]. 

The oxidized form of cytochrome C has a prominent ability to oxidize superoxide, thus returning the escaped electron to ETC and preventing further ROS generation [3]. In contrast, an alternative pathway catalyzed by SOD1 in IMS produces hydrogen peroxide (H2O2), which may cause further cytochrome C oxidation and subsequent peroxidation of mitochondrial membrane phospholipids, including cardiolipin [4]. 

Accumulation of lipid hydroperoxides may promote ferroptosis, as discussed below. To some extent, ROS are always generated during mitochondrial aerobic metabolism for intracellular signaling [5–7] However, redox activity imbalance may result in mitochondrial dysfunction. The excessive production of ROS contributes to oxidative stress and is a prominent part of aging processes and many degenerative diseases, including NDs [8]. 

Oxidative stress has been widely linked to the Aβ and α-synuclein proteinopathies in Alzheimer's disease (AD) and Parkinson's disease (PD), respectively. Previous studies have revealed that Aβ can induce mitochondrial dysfunction [9]. 

Damaged and dysfunctional mitochondria are extensively removed by mitophagy, which is a central mechanism for the maintenance of organelle homeostasis in neural cells [10]. Since neurons rely on oxidative phosphorylation as the main energy source, mitochondrial function is of utmost importance in studies relating to NDs.

2.1. Alzheimer's Disease

Alzheimer's disease (AD) is the most prevalent ND with a multifactorial origin. The disease affects especially the cerebral cortex and hippocampus. The disease's hallmarks are recognized as aggregates of beta-amyloid (Aβ) and tau proteins that cause the deposition of amyloid plaques and neurofibrillary tangles, respectively [11]. 

Aβ originates from the amyloid precursor protein (APP) that can undergo cleavage at different sites either by the non-amyloidogenic or amyloidogenic pathway, while tau aggregation is linked to its hyperphosphorylation [12]. 

Decades-long investigations have shown prominent mitochondrial abnormalities in the brains of AD patients [13]. Consequently, mitochondrial dysfunction is thought to be an early and prominent feature of AD, which is in concert with compromised energy metabolism observed to be evident already before disease onset [14]. 

These findings are based on fluoro-2-deoxyglucose PET imaging that indicates suppressed glucose utilization in the hippocampus and cortex of AD patients in comparison with individuals without dementia [15,16]. 

Consistent with this, disrupted mitochondrial bioenergetics and increased oxidative stress have been demonstrated in AD [17]. The mechanisms behind mitochondrial dysfunction in AD are thought to be related to impaired mitophagy/mitochondrial biogenesis, disturbed ER-mitochondria interaction, abnormal mitochondrial fusion, and fission and axonal transport deficits. 

Accumulation of swollen mitochondria with distorted cristae has been identified in both human AD cases and transgenic animal models of AD [18,19]. On the other hand, peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α), the master regulator of mitochondrial biogenesis, has reduced expression in AD patients and transgenic mouse models of AD [20]. 

In support of mitochondria-associated membrane disturbances, a recent study demonstrated that C99, the C-terminal fragment derived from APP by β-secretase cleavage, is present in mitochondria-associated ER membranes (MAMs). 

Importantly, the level of C99 is increased in AD resulting in reduced mitochondrial respiration [21]. In vitro, overexpression of wild-type or mutant APP caused mitochondrial fragmentation in neuroblastoma cells and primary neurons [22]. 

The fragmentation observed was sensitive to beta-secretase 1 (BACE1) inhibition, suggesting a role of Aβ in excessive mitochondrial fission. 

Furthermore, inhibition of mitochondrial fragmentation with mitochondrial division inhibitor 1 decreased extracellular amyloid deposition, Aβ1-42/Aβ1-40 ratio, and prevented the development of cognitive deficits in a rodent model for AD [23].

Figure 1. Major sources of intracellular reactive oxygen species (ROS) production and their convergence to ferroptosis through the generation of H2O2. (a) In the mitochondria, ETC-produced superoxide is converted to hydrogen peroxide by SOD2 and SOD1. 

Cytochrome C, located in the mitochondrial IMS, may have a dual role by scavenging superoxide or interacting with peroxide and contributing to cardiolipin peroxidation. 

Mitochondrial activity by supporting lipid biosynthesis may enhance ferroptosis. (b) Excessive protein refolding in ER increases PDI/Ero1a activities resulting in a rise in H2O2 production, calcium efflux, NADPH oxidase activation, and general ER stress linked to inflammation. (c) Ferrous iron overload, elevated levels of H2O2, and GPX4 deficiency cause accumulation of lipid peroxides and initiation of ferroptotic cell death. 

ACSL4 and LPCAT3 catalyze the incorporation of PUFA into membranes, thereby sensitizing them to ferroptosis. (d) In peroxisomes, ROS are primarily produced by fatty acid beta-oxidation catalyzed by ACOX. 

Abbreviations: IMS-intermembrane space; ETC-electron transport chain; SOD1-Cu, Zn superoxide dismutase; SOD2-Mn superoxide dismutase; PDI-protein disulfide isomerase; ERO1a-Endoplasmic reticulum oxidoreductase 1 alpha; NOX-NADPH oxidase; GPX4-Glutathione peroxidase 4; PERK-protein kinase RNA-like endoplasmic reticulum kinase; ATF6-activating transcription factor 6; IRE1-inositol-requiring enzyme 1; NFkB-nuclear factor kappa-light-chain-enhancer of activated B cells; TRAF2-TNF receptor-associated factor 2; JNK-c-Jun N-terminal kinase. ACSL4-Acyl-CoA synthetase long-chain family member 4; LPCAT3-Lysophosphatidylcholine acyltransferase 3; PUFA-polyunsaturated fatty acids; ACOX-Acyl-CoA oxidase.

Additionally, mitochondrial distribution is altered in the AD brain due to disturbed axonal transport. The mitochondria have a lower presence in the neuronal processes in the vulnerable AD pyramidal neurons when compared to healthy controls [24].
The abnormal distribution of mitochondria appears to be linked to ROS since increasing acetylation levels of an antioxidant enzyme Prx1 by HDAC6 deacetylase inhibition recovered impaired mitochondrial axonal transport, decreased ROS levels, and Ca2+ disbalance in AD models [25].

2.2. Parkinson's Disease

Parkinson's disease (PD) is the second most frequent neurodegenerative disorder with a multifactorial background. At the histopathological level, it is characterized by the presence of intracellular lesions named Lewy bodies and by exacerbated cell death of dopaminergic neurons [26]. Similar to AD, PD can arise due to genetic causes (familial or heritable) or occur sporadically [27]. 

PD belongs to synucleinopathies and is characterized by disrupted proteostasis of alpha-synuclein (α-Syn) that results from the formation of α-Syn oligomers and fibrils. In vitro investigations of α-Syn in a hypothalamic neuronal cell line GT1-7 revealed that its overexpression caused the formation of inclusion-like structures and mitochondrial deficits accompanied by increased levels of ROS [28]. 

More recent studies have demonstrated α-Syn translocation to the mitochondrial matrix and impairment of ETC complex I causing inhibition of ATP synthesis and a rise in ROS production [29]. 

Additionally, α-Syn oligomers reduced axonal mitochondria transport in induced pluripotent stem cell (iPSC)-derived neurons [30]. Moreover, disturbed mitophagy has been discovered in PD patient neurons, which was linked to abnormal accumulation of Miro protein [31]. 

Recently, the association of α-Syn with mitochondria resulted in decreased levels of mitochondrial SIRT3, and a reduction in mitochondrial biogenesis was demonstrated. This change was accompanied by impaired mitochondrial dynamics and significantly decreased oxygen consumption rate indicating mitochondria respiratory deficit [32].

2.3. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common progressive adult-onset motoneuron disease, characterized by selective death of upper and/or lower motoneurons. The disease leads to paralysis of voluntary muscles and eventually to death. The mechanisms causing neuronal degeneration in ALS are extensively studied, including disturbed motoneuron proteostasis [33]. 

While about 90% of ALS cases are sporadic, the remaining 10% are familial. Within familial ALS, the mutations in the SOD1 gene represent approx. 20% of dominantly inherited familial mutations, which cause the protein to misfold and aggregate. 

Another predominant familial cause for ALS, and also for frontotemporal dementia, is an intronic G4C2 hexanucleotide repeat expansion within the promoter region of chromosome 9 open reading frame 72-C9orf72 [34]. 

Even though the increased risk of ALS due to C9orf72 expansions is well documented, the exact mechanisms by which it causes neurodegeneration are not completely established [35,36]. Recent studies, however, indicate compromised mitochondrial function and bioenergetic deficits as key pathological factors in C9orf72-linked ALS [37,38]. 

Studies on animal models of familial forms of ALS have provided strong evidence for mitochondrial dysfunction in motor neuron degeneration [39–41]. Notably, there is also evidence of similar mitochondrial dysfunction in sporadic ALS cases. 

Analysis of patient autopsy samples has revealed increased mitochondrial density in motor neurons as well as significantly reduced ETC complex IV activity in the gray matter in both cervical and lumbar spinal cords [42]. 

Additionally, gene expression profiling in human induced pluripotent stem cells (iPSC)-derived motor neurons from sporadic ALS patients showed a strong association between mitochondrial functions and neurodegeneration [43,44]. Further studies on sporadic ALS patient iPSC-derived motor neurons have demonstrated that mitochondrial dysfunction in sporadic amyotrophic lateral sclerosis is developmentally regulated [45].

2.4. Huntington's Disease

Huntington's disease (HD) is an autosomal dominant ND with an average onset age of 40 years, characterized by the expansion of polyglutamine repeats in the protein called huntingtin (hit). This leads to a gain of protein function toxic properties in the striatal and cortex neurons, causing motor and cognitive deficits [46]. More than 40 repeats predispose an individual to the disease, whereas less than 26 are tolerated [47]. 

There is a vast amount of research on HD models and patient samples indicating redox imbalance, as is evident from elevated levels of markers of protein oxidation and lipid peroxidation [48]. It has been demonstrated that mutant huntingtin (mhtt) affects the function of proteins and transcription factors related to mitochondrial homeostasis. 

It may cause inhibited expression of PGC-1α, a transcriptional coactivator that is known to regulate mitochondrial respiration and biogenesis [49]. Another line of evidence suggests compromised functioning of ETC manifesting as increased lactate levels and reduced activities of complex II, III, and IV in HD patients' brains [50,51].

3. Link between ER Stress and Neuroinflammation

Intracellular protein accumulation is a hallmark of many NDs, including AD, PD, ALS, and HD [52]. Although the exact role of these protein aggregates in the pathology of neurodegeneration is under debate, one of their outcomes in the brain is endoplasmic reticulum (ER) stress. 

Under physiological conditions, ER is responsible for protein synthesis, posttranslational processing, folding of newly synthesized proteins, and finally delivering the biologically active proteins to their proper target sites. 

Different harmful stimuli, for example, increased oxidation, neuronal aging, or mutations may result in the transcended activity of ER, and ER disruption in the normal physiological state, finally leading to ER stress. 

Recovery to its normal physiological balance requires activation of the unfolded protein response (UPR) signaling pathway. If the UPR fails to restore the cell integrity, cell death signaling cascades are activated and the cell undergoes apoptosis [53]. 

Furthermore, ER stress and UPR signaling are thought to contribute to the pathogenesis of NDs [54]. They can influence inflammation through various mechanisms, such as the production of ROS, the release of calcium from the ER, the activation of a key regulator of the inflammatory response transcription factor nuclear factor-κB (NF-κB), and the mitogen-activated protein kinase (MAPK) known as JNK (JUN N-terminal kinase), and the induction of the acute phase response [55] (Figure 1b). 

In parallel, the ER stress-induced signaling pathway of PERK to translation initiation factor 2α (eIF2α) suppresses protein synthesis and promotes NF-κB-dependent transcription due to an increased ratio of NF-κB to IκB (inhibitor of nuclear factor kappa B) [56]. Moreover, upon ER stress, the interaction of IRE1α with TNF receptor-associated factor 2 (TRAF2) may lead to NF-kB activation [57,58]. 

In general, the mechanisms of ER stress contributing to the neuroinflammation and pathogenesis of particular NDs are not completely understood. Recently, the interplay between UPR and inflammatory pathways has been reviewed in more detail by Sprenkle et al. [59]. 

Depending on the disease type and the specific signaling molecule studied, manipulations of UPR in various disease models have yielded controversial and contrasting results [60]. A recent in vivo study has demonstrated that paraquat-induced ER stress caused a decrease in the number of neural stem cells and enhanced neuroinflammation in both subgranular and subventricular zones [61]. 

Besides aberrant inflammatory signaling described above, sustained ER stress compromises the protective function of the UPR in NDs, leading to the induction of apoptosis-activating pathways and neuroinflammatory activation of glia. A growing body of evidence indicates potential crosstalk between the UPR in immune cells and neuroinflammation [62].

3.1. Alzheimer's Disease

Due to the protein aggregation seen during the disease progression, it is not surprising that several signs of ER stress have been demonstrated both in animal models and in human postmortem samples of AD [63]. Being a disease with a multifactorial nature, AD displays concomitant synaptic loss with ER stress and neuroinflammation, which associate and correlate with the severity of pathology progression [64]. 

The research utilizing iPSC in deciphering the role of ER stress and UPR in AD seems to be scattered, possibly due to the immature or early developmental phase that iPSC-derived models typically represent. However, Kondo et al. have demonstrated ER and oxidative stress in iPSC-derived neurons both in familial and sporadic patients [65]. 

In addition, Oksanen et al. have demonstrated that the pro-inflammatory phenotype of presenilin-1 mutant iPSC-derived astrocytes is associated with elevated calcium leakage from the ER, which is a known hallmark of ER stress [66]. Interestingly, recent studies have discovered that ER stress can also stimulate the innate immune defense to protect the brain [59,67]. 

Despite the extensive work in studying the role of inflammation in AD, no clear answer to the question of how ER stress is linked to inflammation in AD has yet been achieved [68–70].

3.2. Parkinson's Disease

A vast amount of research data has demonstrated the link between ER stress and UPR in PD pathology. Costa et al. [71] summarized the current evidence from post-mortem analysis and from in vivo and in vitro pharmacological and genetic studies. 

However, it is important to remember that the evidence is controversial to some extent. Although inhibition of protein disulfide isomerase (PDI) is commonly seen as a beneficial molecule in ER stress, it can controversially suppress excessive protein folding and ER stress and induce clearance of aggregated α-Syn by autophagy as an alternative degradation pathway. 

These findings suggest a novel model explaining the contribution of ER dysfunction to MPP(+)-induced neurodegeneration, the most common toxin model of PD, highlighting PDI inhibitors as a potential treatment in diseases involving protein misfolding [72]. 

In parallel, ER stress induced in microglia and resulting in their neuroinflammatory phenotype has been implicated in the decrease in neural stem cells in an animal model of paraquat exposure [61].

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