CNS Redox Homeostasis And Dysfunction in Neurodegenerative Diseases Part 2

3.3. Amyotrophic Lateral Sclerosis

The role of ER stress and UPR in ALS is widely studied by utilizing various disease models, such as ALS iPSC lines and animal models, as well as post-mortem ALS samples [54]. Interestingly, recent studies have demonstrated that misfolded protein accumulation increases PDI levels, promoting the cell death cascade [72,73]. 

Protein is an important component of our body. It is not only an important component of our muscle tissue and organs but also one of the nutrients necessary for our brain activities. Studies in recent years have shown that protein also plays an important role in our memory. The following is the relationship between protein and memory.

First, protein can promote the development of neurons, thereby improving memory. Neurons are the basic units in the brain, responsible for transmitting information and controlling various activities. If the number of neurons increases or the connection between neurons is closer, people's memory will be better. Protein can accelerate the growth and differentiation of neurons, thereby promoting brain development and improving our memory.

Secondly, protein can also increase the content of neurotransmitters in the brain and improve people's thinking ability. Neurotransmitters are chemicals used to transmit information in the brain, which directly affects our thinking, learning, and memory. Protein can promote the synthesis and release of neurotransmitters, so that the content of neurotransmitters in the brain is more sufficient, accelerate the speed of information transmission, and enhance our thinking ability.

Finally, protein can also improve people's mood and promote their memory. Mood is an important factor affecting memory. If the mood is low, people's memory will be affected. Protein can promote the synthesis of tyrosine in the body, thereby improving people's mood, enhancing enthusiasm and emotional stability, and improving our memory.

Therefore, we can see that protein plays an important role in promoting brain development, increasing neurotransmitter content, and improving mood, thereby promoting our memory. It is recommended that you pay attention to protein intake in your daily diet and choose high-quality protein foods, such as chicken, fish, dairy products, etc., to meet the needs of the body and improve your memory. At the same time, a healthy lifestyle and a good mood can have a positive impact on memory, allowing us to live a healthier and happier life. It can be seen that we need to improve our memory, and Cistanche can significantly improve memory, because Cistanche can also regulate the balance of neurotransmitters, such as increasing the levels of acetylcholine and growth factors, which are very important for memory and learning. In addition, Cistanche can also improve blood flow and promote oxygen delivery, which can ensure that the brain obtains sufficient nutrition and energy, thereby improving brain vitality and endurance.

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In line with these findings, our lab has shown that UPR may lead to activation of PDI-dependent NADPH oxidase (NOX) and thus contribute to neurotoxicity in ALS [74]. In addition, the lack of XBP1 (X-box-binding protein-1), a key UPR transcription factor that regulates genes involved in protein folding and quality control, has been shown to increase survival in an ALS mouse model [75] thus demonstrating the dual role of UPR in neurodegeneration.

3.4. Huntington's Disease

Experimental evidence suggests that cytosolic mhtt protein fragments impair ERassociated protein degradation (ERAD) by entrapping ERAD proteins [76]. Consequently, misfolded proteins accumulate in the ER and cause ER stress. 

To counterbalance this accumulation, the UPR activates the proteasome degradation pathway and upregulates the transcription of chaperones [77]. Recent studies also suggested the interconnection between ER stress and UPR activation, leading to inflammatory processes [55]. Especially activated microglia and secreted inflammatory cytokines could lead to axonal damage and contribute thus to neuronal cell death in HD [78,79]. 

Overall, protein homeostasis maintenance is crucial for preventing mhtt-related toxicity, and modulation of the UPR pathway with specific inhibitors or activators could be the most effective therapeutic approach in the future.

4. Redox Imbalance and Protein Misfolding in Neurodegeneration

A vast proportion of translated proteins pass through the ER for tertiary modifications and ensure correct folding. Cells have an autoregulatory mechanism that detects and corrects misfolded or unfolded proteins that are sent to the ER [80]. 

Inside the ER, enzymes, and chaperone proteins can help ER-imported proteins fold correctly by cleaving unfavorable intramolecular bonds or by helping to form new ones [80,81]. These modifications remarkably speed up the folding process, in which proteins fold into their native conformations. 

The ER also has a mechanism to detect a rise in the proportion of misfolded proteins in the ER, and when such an increase is detected, a downstream signaling pathway known as the UPR is launched to compensate for the need for more quality control proteins such as chaperones [82]. The overall role of UPR is to relieve a cell from ER stress and re-establish homeostasis. 

Three main routes become activated in the UPR, defined by different classes of transmembrane ER-resident signaling proteins. These three paths are mediated by the activating transcription factor 6 (ATF6), inositol-requiring enzyme 1 (IRE1), and the double-stranded RNA-activated protein kinase (PKR)-like ER kinase (PERK) [53]. 

UPR-activating transmembrane proteins are vastly studied in basic cellular biology and ER function, and they are prominent in the spectrum of protein misfolding-related NDs. The levels of proteins inside cells are determined not only by synthesis but also by degradation rates, eliminating the consequences of faulty protein synthesis. 

Two major degradation pathways exist-the ubiquitin-proteasome pathway (UPP) and lysosomal proteolysis. In the UPP, the proteins for degradation are marked by ubiquitin attachment to the amino group of the side chain of a lysine residue [83]. After polyubiquitinated proteins are degraded in proteosomes, ubiquitin can be released and reused for another cycle. 

The clearance of misfolded proteins in NDs is primarily exercised by the UPP [84]. The second major pathway of protein degradation involves degradation in lysosomes. 

The proteins that are degraded by this pathway are long-lived cytoplasmic but dispensable proteins. Under physiological conditions, all three UPR sensors are negatively regulated by the ER chaperone glucose-regulated protein 78/binding immunoglobulin protein (GRP78/BiP), which suppresses their activity by binding to their luminal ends [85]. When cells undergo constant ER stress, BiP dissociates from UPR sensors inducing their activation and thus promoting protein refolding and degradation of misfolded/unfolded proteins. 

However, under chronic ER stress, UPR sensors shift their signaling toward induction of cell death by apoptosis [81]. All three ER transmembrane proteins have an important control role in cell fate, where they can either help the cell survive in conditions that produce ER stress or trigger apoptotic pathways when the cells sense that the pressure for extensive UPR is too high [86,87]. 

While the three ER proteins are perhaps the single most important molecules in the aftermath of ER stress, cells also have another mechanism to sense the ER stress state. These other mechanisms are pooled together in the non-canonical ER stress response, including ERAD, ER-related autophagy, and integrated stress response (ISR), respectively, which are thought to play an important role in NDs [88]. 

In the ER, redox balance is coupled to protein folding as well as cellular calcium homeostasis. Acute swings and prolonged changes in the redox balance can impair the cell's capability to handle misfolded protein. The redox imbalance and protein misfolding can enhance each other and synergistically result in chronic ER-stress-related neurodegeneration [89]. 

Oxidation is used in the ER to help form a disulfide bond in an oxidative protein-folding manner. The disulfide structures in a molecule are rearranged continuously by chaperone proteins such as PDI until the disulfides in a folding protein have obtained native conformation [90]. Oxidation of PDI is coupled with the reduction of Ero1 (Figure 1b). 

PDI can act also as an isomerase for the disulfide bridges already present in the folding proteins, changing their conformation. The redox state of the CGHC motif of a PDI molecule determines whether the PDI acts as an oxidase or as an isomerase [74,91]. The levels of glutathione (GSH) indicate the oxidative balance of ER or cytosol and low levels of cytosolic GSH have been demonstrated in models of human NDs. 

The GSH and its oxidized form glutathione disulfide (GSSG) are present in the ER from 1:1 to 1:3 ratio (GSH/GSSG) compared to the >50:1 ratio present in the cytosol, due to the highly oxidative environment of the ER [92,93]. Protein misfolding, ER stress, and redox state leading to neurodegeneration are common problems in a range of NDs, including AD, PD, ALS, and HD [94–96]. As reviewed by Hetz and Saxena (2017), maybe the most represented disease involving redox imbalance and protein aggregation is ALS [96].

4.1. Alzheimer's Disease

Oxidative stress and redox imbalance, as shown by increased levels of lipid peroxidation end product 4-hydroxy-2-nonenal (4-HNE), are early events in AD pathogenesis [97,98] that precede amyloid plaque formation [99]. Accordingly, 4-HNE has been implicated in promoting the formation of more toxic Aβ protofibrils [99]. Another piece of evidence for the role of oxidative stress and protein misfolding in AD is the finding that 4-HNE or Fe2+ can enhance the activity of β-secretase and thus increase the production of pathological Aβ42 [100]. 

This could be linked to the fact that Aβ40/42 can directly increase H2O2 production by metal transductors Fe3+ or Cu2+, creating a positive feedback loop in the presence of metal ions [101]. Metals such as Zn, Fe, and Cu have been observed to be enriched in amyloid plaques of AD patients and their significance has been reviewed elsewhere [102]. Interacting with metals is not the only way that Aβ has been shown to induce oxidative stress, as the soluble oligomers of Aβ and amyloid-beta precursor protein (APP) can inhibit the production of GSH by blocking the cysteine uptake through the EAAT3 receptor [103,104]. 

On the other hand, the generation of 4-HNE may induce an antioxidant response through activation of the Nrf2/Keap1 pathway [105]. It has been demonstrated that this pathway is particularly stimulated by the supplementation of docosahexaenoic acid (DHA) [106]. In concert with this, several recent studies indicate that long-chain polyunsaturated fatty acid-containing phospholipids are affected in AD, where depletion of DHA is the most prominent [107–109]. 

In parallel, studies on ER stress contribution to AD have demonstrated immunostaining against UPR markers such as pERK, elF2α, and IRE1α in the hippocampus. All these markers were correlated with intracellular Tau hyperphosphorylation in the hippocampal area, though surprisingly not with amyloid fibrils [110,111].

4.2. Parkinson's Disease

In PD, intracellular fragmented compartments named Lewy bodies are a common finding and possibly the leading cause of PD, Lewy body dementia, and multiple system atrophy. Inside the Lewy bodies, the most prevalent protein is aggregated α-Syn, which can be found in a heterozygous pool of different-sized fibrils, intermediate species, and native monomers. The α-Syn is a small (14.5 kDa) protein with a fluctuating C-terminal and lipid membrane interacting middle-section and N-terminal. In a titration protein association assay, PDI was shown to bind monomeric α-Syn after 48 h incubation and with low dissociation constants with earlier time points [112]. In the same study, PDI was also shown to inhibit the fibrillization of α-Syn monomers. Further investigations showed that N-terminal residues V3-S9 and L38-V40, and residues at the C-terminus 123–127 and 135–137 of a wildtype α-Syn monomer interact with PDI [113]. They also confirmed inhibited fibrillization by PDI. Later, it was also shown that PDI can break down nascent α-Syn fibrils, yet not mature fibrils [114]. The redox balance in the ER impacts the S-nitrosylation state of PDI [115]. Interesting results have pointed out the importance of s-nitrosylation of PDI (SNO-PDI) towards α-Syn aggregation and Lewy body formation. 

In the PC12 cell line, treatment with a strong antioxidant ellagic acid prevented SNO-PDI and thus prevented the aggregation of α-Syn, synphilin-1, and α-Syn-synphilin-1 composites, also characterized as Lewy-like neurites [116]. Similar results have confirmed the importance of SNO-PDI for the aggregation of α-Syn [117]. The research revolving around protein folding regulation, PDI, and NDs is vivid and highlights the importance of oxidative status for such chaperone molecules that have dual activity. Even though the activity of PDI has been considered beneficial as it protects from protein misfolding accumulation, the excess activity of PDI can also be deleterious. 

A PDI redox state-coupled protein, Ero1a, can take an electron from oxygen, resulting in the formation of H2O2, an important oxidation producer in the ER. Ero1a can donate the electron along to PDI, resulting in a reduced form of PDI. On the other hand, Ero1a can receive the electron from PDI and form oxygen [118]. Our study demonstrated that inhibiting PDI or its redox regulator Ero1α exhibited neuroprotective properties in cell culture and C. elegans MPP+-induced toxicity models [72]. The inhibition of PDI or Ero1α by bacitracin or EN460, respectively, prevented MPP+-induced toxicity and α-Syn accumulation in the ER lumen. Moreover, it caused the clearance of aggregated α-Syn by autophagy. Similarly, treatment of iPSC-derived dopaminergic neurons carrying the GBA-N370S PD risk variant with tasquinimod, an allosteric inhibitor of HDAC4 or cantharidin, a protein phosphatase-2 inhibitor, reduced the α-Syn release, promoted autophagy, and ameliorated ER stress [119]. 

Like in AD, the presence of metals has been linked to protein misfolding and redox imbalance also in PD. The mechanism by which α-Syn oligomers induce ROS generation is related to redox metal ions and can be suppressed by the chelation of free iron or copper [120]. Moreover, it is known that metals also induce α-Syn aggregation [121]. 

Questions remain whether α-Syn interaction with metals causes fibrillization and then produces oxidative stress or whether α-Syn together with metal chelators first produces oxidative stress that promotes fibrillization since there is the possibility that α-Syn fibrillization is a protective mechanism for toxic soluble oligomeric forms of α-Syn. All forms of α-Syn fibrils are known to interact with multiple different lipid formations and intracellular molecules. In the scope of oxidative stress findings where α-Syn is shown to interact with SOD1 and promote its oligomerization, it further links the α-Syn to an oxidative imbalance present in PD and in ALS [122].

4.3. Amyotrophic Lateral Sclerosis

In ALS studies, it has been demonstrated that the mutated SOD1 increases the expression of PDI in the ER and downregulates the ERAD pathway, indicating misfolding protein-induced ER stress [123]. Additionally, PDI upregulation can slow down the aggregation of SOD1 and dysfunctions of PDI, thus affecting the disease progression. In sporadic and familial ALS cases, PDI immunostaining correlated with the affected neurons [124]. Moreover, activation of UPR in both sporadic and familial forms of ALS has been demonstrated [123,125]. It is not thus surprising that clinical trials of a compound inhibiting eIF2α dephosphorylation for ALS treatment are ongoing [126,127]. elF2α is an important translation initiation factor and regulator of the integrated stress response.

4.4. Huntington's Disease

While oxidative stress does not necessarily lead to protein misfolding or other pathological insults in HD since the disease is caused by genetics, the pathological protein huntingtin is involved in the misbalance of oxidative regulation and redox signaling. While the exact mechanism is still elusive, disruption of the antioxidant defense mechanism has been linked to HD pathophysiology [128]. In mice, treatment with mitochondria-targeted antioxidant MitoQ reduced markers of oxidative damage in muscle and significantly ameliorated fine motor control of R6/2 mice supporting the hypotheses that abnormal redox signaling in muscle contributes to altered proteostasis and motor impairment in HD [129].

5. Ferroptosis

Ferroptosis is a relatively recently discovered iron-dependent cell death mechanism, characterized by phospholipid peroxidation (Figure 1c). It is a regulated, non-apoptotic, intra-cellular cell death pathway [130,131]. Ferroptosis depends on the presence of intracellular free iron (Fe2+) and GSH-dependent activity of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) activity, which upon its reduced activity causes accumulation of lipid peroxides and initiation of ferroptotic cell death (Figure 1c). 

The intracellular morphological hallmarks of ferroptosis include the shrinkage of mitochondria, an increased mitochondrial membrane density or rupture of the outer membrane, as well as a reduced number of mitochondrial cristae. Additionally, it is complemented by plasma membrane rupture, rounding of the cell due to cytoplasmic swelling, and cell volume loss [132]. Under physiological conditions, iron is taken up by mitochondria and ligated by heme into FeS clusters or ferritin, a protein that stores iron intracellularly [133]. 

Nevertheless, heme catabolism also provides free iron (ferrous, Fe2+) for the Fenton reaction. Free and loosely bound intracellular iron that plays a central role in ferroptosis is assumed to enter the Fenton chemistry reactions, in which H2O2 is decomposed into harmful hydroxyl radicals. Fenton chemistry is a self-propagating chain reaction composed of the Haber– Weiss reaction and the Fenton reaction itself. In the Fenton reaction, Fe2+ reacting with H2O2 yields ferric iron (Fe3+) and hydroxyl radical (HO•). Next, hydroxyl radical reacts with H2O2 to produce superoxide (O2 −). In the following Haber–Weiss reaction, superoxide reacts with H2O2 to produce HO• and hydroxyl anion (-OH). 

This is catalyzed by the reduction of Fe3+ to Fe2+, which in turn enters the Fenton reaction. The produced HO•s are strong initiators of lipid peroxidation [134–136]. These reactions can be quenched if enough radicals are formed so that they can react with each other by forming a bond and eliminating the radicals. Another way to stop the chain reaction is through antioxidative molecules [130,137]. The mechanisms above have high relevance for NDs such as AD and PD, where the accumulation of iron and oxidative stress are associated with degenerative pathology [138]. 

Besides the contribution of Fenton chemistry to lipid peroxidation, ROS/ reactive nitrogen species (RNS) interfere with proteins that regulate iron homeostasis through iron storage/release, thereby increasing the Fe2+ load. Fe2+ further interferes with the regeneration of endogenous GSH [134,135], hence GPX4 activity. The latter plays a central role in the protection of membrane lipids from peroxidation and is the most distinctly expressed GPX isoform in the brain [109,139]. By alternative splicing, cytoplasmic, nuclear, and mitochondrial isoenzymes of GPX4 are produced [139,140]. DHA plays an important role in GPX4 transcriptional regulation, and it has been demonstrated to induce GPX4 expression, particularly the cytoplasmic form, in brain cells [106,141]. Taken together, ferroptosis is mainly induced by the accumulation of Fe2+, depletion of GSH, and inhibition of GPX4 activity [142]. 

In the brain, iron overload may cause lipid peroxidation in neurons and glial cells, as well as GPX4 deficiency, as iron overload is linked to motor neuron degeneration [143,144]. The relevance of ferroptotic cell death is further emphasized by its contribution to neuroinflammation. There is a multifaceted association between ferroptosis, arachidonic acid (AA) metabolism, and pro-inflammatory mediators [145]. 

The inflammation upon ferroptosis is triggered by the release of pro-inflammatory mediators and pro-inflammatory polarization of microglia/macrophages, the release of damage-associated molecular patterns (DAMPs), and immunogenic lipid metabolites [146–148]. Several pro-inflammatory factors released, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β), may provide positive feedback to ferroptosis by mediating neuronal iron uptake followed by sustained down-regulation of GPX4 activity [149,150]. In concert with this, inhibition of ferroptosis has been shown to decrease microglial activation and suppress the release of IL-6, IL-1β, and TNF-α [145].

Recently, ferroptosis has gained a lot of attention as a mechanism behind brain diseases, including NDs. Importantly, in NDs, ferroptosis appears to be driven by redox imbalance [151,152], and the intracellular pathways involved in ferroptosis allow us to distinguish various druggable targets [153].

5.1. Alzheimer's Disease

Despite characteristic pathological hallmarks of AD, including Aβ plaque and neurofibrillary tangles, the mechanism of neurodegeneration remains largely obscure. Since phospholipid peroxidation is apparent in AD patient brain samples, a growing body of evidence indicates the involvement of ferroptotic mechanisms in the pathogenesis of AD [154]. Elevated iron concentration was found in clinic-pathological examinations of AD cases many decades ago and targeting iron has been proposed as a disease-modifying therapy for AD [155]. On the other hand, there have been studies demonstrating the binding of iron to Aβ and tau while promoting their aggregation [156]. Since then, a meta-analysis of 300 AD cases from 19 studies has indicated the heterogeneous distribution of elevated iron levels in AD brain cortical areas, particularly in the putamen and amygdala [157]. 

Moreover, hallmarks of eventual ferroptosis as GSH depletion, lipid peroxidation, and protein carbonyls have been found in post-mortem AD brain samples [158,159]. So far, several mechanisms have been proposed for linking iron with AD pathophysiology. First off, the amyloidogenic processing of APP may destabilize ferroportin, a protein responsible for iron efflux, thus leading to an elevated neuronal iron burden [160]. Next, pathological interaction between Aβ and iron may result in aberrant iron redox chemistry, leading to oxidative stress and cognitive deficits in AD [156]. In parallel, iron can promote tau hyperphosphorylation by induction of glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase 5 (Cdk5) [161]. Finally, a correlation between enhanced neuronal default mode network activity in apolipoprotein E4 (APOE4) carriers and cortical iron burden has been demonstrated, suggesting that the interaction between APOE4 and iron may result in affected brain functions [162].

5.2. Parkinson's Disease

In PD, several pathological hallmarks are consistent with ferroptosis [163]. Among them, hypermethylation-associated downregulation of cystine-glutamate antiporter SLC7A11 gene [164], the elevation of lipid peroxidation products [165], increased iron concentrations, and decreased GPX4 activity in substantia nigra [166,167], and DJ-1 depletion rendering neurons susceptible to the ferroptosis [168] are evident in PD models and are linked to PD pathogenesis. Importantly, moderate iron chelation has shown promising therapeutical effects in PD patients [169]. A functional link between ferroptosis and PD may be related to disturbed α-Syn proteostasis, which is associated with iron and lipid metabolism [163].

5.3. Amyotrophic Lateral Sclerosis

Markers for oxidative stress and lipid peroxidation, such as malondialdehyde, 4-HNE, protein carbonyls, and oxidized membrane phospholipids, have been found in animal models and samples from familial and sporadic ALS cases [170,171]. Importantly, deficiency in ferroptosis-suppressing GPX4 in neurons causes motor neuron degeneration and paralysis [143]. In contrast, overexpression of GPX4 in mutant SOD1G93A ALS model mice slows down disease progression [172]. Moreover, investigations on ferroptosis inhibitors, such as CuII(atsm), have recently shown positive results for phase 1 studies in ALS patients [173].

5.4. Huntington's Disease

There is emerging evidence regarding the contribution of ferroptosis to HD pathology [174]. Most importantly, MRI imaging of HD patients has revealed increased iron deposition in several brain regions [175], and ferroptosis inhibitors, such as ferrostatin-1, exert positive effects on animal models of HD [176]. The mechanism of how the expression of that is linked to the induction of ferroptosis may include interactions with the outer membrane of mitochondria and disturbances of calcium homeostasis [177], augmented mitochondrial fragmentation [178], and disturbed import of mitochondrial proteins [179]. Additionally, that may interfere with iron endocytosis, thus leading to its increased accumulation [180].

6. Conclusions

CNS redox imbalance originating from mitochondrial and/or ER sources affects neural cell function, both in terms of viability and pro-inflammatory reactivity. As an outcome, it may trigger necroptotic cell death. Since being recognized as having high relevance for several NDs, ferroptosis has attracted great interest as an opportunity to develop treatments for incurable NDs, such as AD, PD ALS, and HD. There have already been considerable efforts to develop small-molecule ferroptosis inhibitors, particularly indicated for ALS, PD, and AD [137,173,181].

Author Contributions: J.K. and G.G. outlined the review; G.G. coordinated the writing, wrote the introduction and conclusion and AD part and edited its first version and drew the illustration; V.H. and Š.L. wrote the first version about Parkinson's Disease, M.J. about ALS, and M.H.K. about ferroptosis; J.K. edited the first and last version of the manuscript. All authors have read and agreed to the published version of the manuscript.

Funding: This research was funded by the Academy of Finland, Grant number 334525 (J.K.), Sigrid Jusélius Foundation (Š.L.), and Jane and Aatos Erkko Foundation (Š.L.).

Acknowledgments: Open access funding provided by the University of Helsinki.

Conflicts of Interest: The authors declare no conflict of interest.

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