About this Journal Submit a Manuscript Table of Contents
Oxidative Medicine and Cellular Longevity
Volume 2013 (2013), Article ID 408681, 12 pages
http://dx.doi.org/10.1155/2013/408681
Review Article

Redox Regulation in Amyotrophic Lateral Sclerosis

1Department of Biochemistry, La Trobe Institute for Molecular Science, La Trobe University, Vic 3086, Australia
2School of Psychological Science, La Trobe University, Vic 3086, Australia
3Florey Department of Neuroscience, University of Melbourne, Parkville, Vic 3010, Australia

Received 17 October 2012; Revised 7 January 2013; Accepted 10 January 2013

Academic Editor: Jeannette Vasquez-Vivar

Copyright © 2013 Sonam Parakh et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that results from the death of upper and lower motor neurons. Due to a lack of effective treatment, it is imperative to understand the underlying mechanisms and processes involved in disease progression. Regulations in cellular reduction/oxidation (redox) processes are being increasingly implicated in disease. Here we discuss the possible involvement of redox dysregulation in the pathophysiology of ALS, either as a cause of cellular abnormalities or a consequence. We focus on its possible role in oxidative stress, protein misfolding, glutamate excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagic stress, and endoplasmic reticulum (ER) stress. We also speculate that an ER chaperone protein disulphide isomerase (PDI) could play a key role in this dysregulation. PDI is essential for normal protein folding by oxidation and reduction of disulphide bonds, and hence any disruption to this process may have consequences for motor neurons. Addressing the mechanism underlying redox regulation and dysregulation may therefore help to unravel the molecular mechanism involved in ALS.

1. Introduction

Cellular oxidation/reduction (redox) states regulate various aspects of cellular function and maintain homeostasis [1]. Moderate levels of reactive oxygen species/reactive nitrogen species (ROS/RNS) function as signals to promote cell proliferation, regulation, and survival [2], whereas increased levels of ROS/RNS can induce cell death [1, 2]. Under normal physiological conditions, cells maintain redox homeostasis through generation of ROS which include free radical species such as superoxide ( ) hydroxyl radicals (OH) and nonradical species such as hydrogen peroxide (H2O2); and RNS, which includes nitric oxide (NO), nitronium ion ( ), nitrogen dioxide ( ), and peroxynitrite (ONOO) [35]. RNS are by-products of nitric oxide synthase (NOS) and NADPH oxidase [6]. Increased levels of NOS have been observed in the motor neurons of amyotrophic lateral sclerosis (ALS) patients suggesting a role of RNS in pathology [7]. Higher levels of RNS can react with other free radicals such as superoxide and undergo complex reactions to form the strong oxidant ONOO which causes cellular damage [810].

Cells are equipped with antioxidant systems to eliminate ROS/RNS and maintain redox homeostasis, which include enzymatic antioxidants such as superoxide dismutase (SOD), peroxidase, oxidase, catalase, and nonenzymatic oxidants such as glutathione [3, 11]. Glutaredoxin and thioredoxin are redox active molecules which undergo cysteine dependent modifications, also making them preferential targets for direct oxidation [12].

Redox regulation is a fundamental cellular process involving enzymes that maintain the appropriate environment for metabolic activities and proper functioning of the cell [13]. Normally, redox homeostasis ensures that cells respond to stressors such as oxidative or nitrative stress efficiently but when it is disturbed, neurodegeneration and apoptosis can occur [11, 14]. Neurons are particularly susceptible to degeneration via redox dysregulation as the high consumption of oxygen by the brain results in a significant production of ROS [15]. Disruption in redox regulation is implicated in the pathogenesis of neurodegeneration disorders, including ALS. Interestingly, several pathogenic mechanisms linked to ALS involve redox-sensitive proteins, such as SOD1, and proteins with active-site cysteine residues, including protein disulphide isomerase (PDI), thioredoxin, and glutathione [1620]. These proteins contain a thiol group which is highly sensitive to changes in redox conditions [12, 21]. Even slight modulations in redox state are capable of producing neurotoxic species such as , , and ONOO [14], suggesting that redox stress could be of importance in disease [9].

2. Amyotrophic Lateral Sclerosis (ALS)

ALS, also known as Charcot’s or Lou Gehrig’s disease, is a fatal neurodegenerative disorder that affects the upper and lower motor neurons of the primary cortex, brainstem, and spinal cord [22, 23]. The symptoms include muscle weakness and muscle spasticity eventually resulting in paralysis [24] with ALS patients generally dying from respiratory failure within 3–5 years of diagnosis. Approximately 2 per 100,000 people worldwide are affected by ALS every year [22]. Riluzole is the only FDA-approved drug currently available for ALS. Riluzole has modest efficacy. It slows disease progression and a dose of 100 mg per day also improves limb function and muscle strength although it increases life span by an average of only 2-3 months [25, 26]. Therefore, a greater understanding of the molecular mechanisms causing ALS is important in order to develop better therapeutic solutions.

Approximately 90% of ALS cases have no genetic association and are known as sporadic ALS (SALS). However mutations in genes such as copper/zinc superoxide dismutase (SOD1), fused in sarcoma (FUS) and TAR DNA binding protein (TARDBP), have also been described in SALS patients; also environmental causes such as smoking and viral infection are linked to ALS [24, 2731]. Studies have shown higher prevalence of ALS in people with a history of trauma [32] and involvement in physical activities such as soccer has also been observed in ALS patients [33, 34]; however the exact aetiology is unknown. The remaining 10% of ALS cases, known as familial ALS (FALS), are linked to mutations in specific genes [35] including SOD1, TDP-43, FUS, vesicle associated membrane protein-B (VAPB), optineurin, alsin, and ubiquilin-2 [18, 3643]. Recently a noncoding mutation in C9ORF72 was shown to cause the greatest proportion of FALS cases [44]. SOD1 causes 15–20% of all FALS cases and was the first described and hence most widely researched gene linked to ALS [18]. Transgenic mice overexpressing ALS-associated mutant SOD1 proteins have been used extensively as disease models [4547]. Similar to other protein disorders, the pathological hallmark of ALS is the presence of intracellular protein inclusions [48]. Misfolded wild-type and mutant forms of SOD1, FUS, and TDP-43 [41, 49, 50] are present on the inclusions found in affected tissues of ALS patients [41, 5153]. SALS and FALS have similar symptoms and are clinically and pathologically indistinguishable.

Wild-type SOD1 is a highly stable homodimeric protein, explained in part by the presence of an intrasubunit disulphide bond between cysteine 57 and cysteine 146 [54]. It contains both copper and zinc ions which are essential for the catalytic activity and stability, respectively [55]. Reduction of the disulphide bond results in dissociation of the dimer and the resulting protein is highly unstable and prone to aggregation [56, 57].

Dysfunction in multiple cellular mechanisms is linked to ALS pathology reviewed recently by Cozzolino and coworkers [58]. Many of these events are linked to redox regulation including oxidative stress, protein misfolding and aggregation, excitotoxicity, lipid peroxidation and cholesterol esterification, mitochondrial dysfunction, impaired axonal transport and neurofilament aggregation, autophagy, and ER stress [46, 5968]. However, there is a complex interplay between these processes and the exact aetiology of the disease is unclear. It is debatable whether redox dysregulation is a primary effect or a secondary consequence of other pathologies and the association of redox regulation and cysteine rich redox regulated proteins with these mechanisms is unclear. This paper discusses the main redox linked mechanisms which are involved in ALS and their association with redox or cysteine dependent proteins.

3. Possible Redox Regulated Cellular Mechanisms Involved in ALS

3.1. Oxidative Stress

Oxidative stress arises when the levels of ROS/RNS exceed the amounts required for normal redox signalling. While oxidative stress has been implicated as a pathological mechanism in ALS the exact role of ROS/RNS in disease processes is unclear [9, 69]. ROS causes permanent oxidative damage to major cellular components such as proteins, DNA, lipids, and cell membranes [7072]. ROS has been detected in the spinal cord and cerebrospinal fluid (CSF) of SALS patients [17]. Increased levels of H2O2 and oxidative damage to protein and DNA have also been observed in SOD1 transgenic mice [73]. Defects in the Rac/Nox pathway leading to redox dysregulation are also linked to SOD1G93A mice [74]. Furthermore dysregulation of redox regulated-tumour protein 1, ubiquitin carboxyl-terminal hydrolase isoenzyme L1, and αB crystallin has been observed in transgenic SOD1G93A mice [75].

Altered redox homeostasis regulates gene expression of transcriptional factors such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), activator protein 1 (AP-1), and hypoxia inducible factor 1α (HIF-1α) [76]. These transcriptional factors help in maintaining homeostasis by regulating gene expression. They have a redox regulated cysteine residue at their DNA binding site [76] which can be affected due to thiol oxidation and could be influenced by ROS [77]. A direct relation between the transcription factors and redox regulation in ALS is unknown; nevertheless dysregulation in the levels of NF-κB and HIF-1α has been observed in SALS patients, and activation of AP-1 in mutant SOD1 expressing cells, suggesting potential involvement of redox regulation in ALS pathology [78, 79].

SOD1 and its antioxidant properties have been studied extensively from the perspective of redox regulation in ALS [80, 81]. SOD1 catalyses the conversion of superoxide into hydrogen peroxide and oxygen and it undergoes cyclic reduction and oxidation of its copper ions [82]. Initially, it was proposed that ALS mutations in SOD1 result in the loss of its ability to act as an antioxidant, but further research showed that disease is not associated with its enzymatic activity [83]. However, mutations in SOD1 could produce ONOO or OH and lower its ability to catalyse superoxide [84] by reacting with nitric oxide [85]. These intermediate products are highly unstable and have been detected with other amino acids such as tyrosine. Nitrated proteins and high levels of nitrotyrosine have been detected in the CSF of both SALS and FALS patients suggesting that posttranslational modification via free radical production is present in ALS [17, 8688]. Oxidised wild-type SOD1 in the lymphoblasts of SALS patients associates with mitochondrial Bcl-2 which causes mitochondrial damage [89]. Oxidative damage is an important phenomenon; however, treatment with antioxidants has not been very successful [90].

3.2. Protein Aggregation and Misfolding

Redox dysregulation may not only increase the production of ROS/RNS but also affect protein conformation and structure. Posttranslational modification of SOD1 such as oxidation has an adverse effect on the conformational arrangement of SOD1 [91]. Glutathionylation, a posttranslational modification of the 111 cysteine residue, causes destabilisation of SOD1 structure [92]. Wild-type SOD1 has been shown in inclusions of SALS patients suggesting its involvement in causing neurotoxicity [93]. Evidence suggests that oxidised wild-type SOD1 has the ability to misfold and form aggregates and gain similar conformation as the mutant and has toxic functions in vitro [89, 94]. SOD1 depleted zinc and copper have altered redox activity and are more prone to oxidation [95].

An oxidising environment also causes abnormal disulphide linkages and protein aggregation in ALS [80, 96]. SOD1 containing aberrant disulphide bonds involves the normally unpaired cysteine residues cysteine 6 and cysteine 111 in the spinal cord of ALS transgenic mice models [96]. Studies show that mutant TDP-43 aggregation is caused due to increased disulphide bonds [97]. Similarly oxidative stress causes aberrant disulphide cross-linking and subcellular localisation of TDP-43 [97] as well as accumulation of FUS into the cytoplasm [98]. Mutant SOD1 readily forms monomers, oligomers, or inclusions which are insoluble [55]. It is unclear how conformational changes cause misfolding but one possible explanation could be the modification and alteration of protein structure by ROS through oxidisation of the thiol group, forming aberrant disulphide bonds.

3.3. Glutamate Excitotoxicity

The levels of glutamate present in mammalian CNS are much higher than those of other neurotransmitters (5–10 mmol/kg) indicating the importance of glutamate in neuronal function [99]. However, excitotoxicity occurs when the levels of glutamate are increased in neurons, resulting in increased calcium intake and neuronal injury [100, 101]. Motor neurons are particularly susceptible to high levels of glutamate [102]. Glutamate uptake from the synapse is controlled by glutamate transporters astroglial GLAST, GLT1, and neuronal EAAC1 which possess a redox regulated cysteine residue [103]. N-methyl-D aspartic acid (NMDA) glutamate receptors are also redox regulated suggesting that redox dysfunction may further affect glutamate regulation. Increased levels of intracellular glutamate and decreased uptake of glutamate from the synapse have been observed in ALS patients [104, 105]. Indeed, Rothstein and coworkers showed an absence of GLT1 transporter in ALS patients [106]. ROS can reduce the uptake of glutamate in mammals [107]; however, increased calcium levels in the mitochondria due to dysfunctional glutamate regulation can result in overproduction of ROS and cause oxidative stress [108]. The question remains whether oxidative stress causes glutamate dysregulation or vice versa.

3.4. Lipid Peroxidation and Cholesterol Esterification

The ER is also the main site of lipid and sterol synthesis [109]. Lipids are major targets of oxidative stress, resulting in lipid peroxidation via a chain-reaction process [11]. Sphingolipids are localised in the plasma membrane and ER membranes and, with cholesterol, are processed into domains known as lipid rafts [68]. Lipid rafts can form macroplatforms for redox signalling, providing critical mediation for cellular functioning [110]. Lipid peroxidation and cholesterol esterification have been implicated in the pathogenesis of ALS [68, 69, 111]. Excitotoxicity and oxidative stress alter sphingolipid metabolism resulting in the accumulation of long-chain ceramides, sphingomyelin, and cholesterol esters in the spinal cords of ALS patients and Cu/Zn SOD1 mice. This occurs at the early presymptomatic stage of disease in the SOD1 mice [68] thus implicating aberrant lipid metabolism in the pathophysiology of ALS. Further evidence of lipid dysregulation in ALS comes from studies which reported that ALS patients demonstrated a tendency towards hyperlipidemia. Additionally, correlational studies have shown that ALS patients with the highest low density lipoprotein (LDL)/ high density lipoprotein (HDL) ratio have a significant increase in survival time and respiratory function [112, 113]. Furthermore, recently, an interaction between SOD1 aggregates with lipid was found to alter lipid membrane permeability [114].

Lipid peroxidation products such as 4-hydroxynonenal have been detected at higher levels in ALS patients spinal cord than controls, and this has been linked to modification of astrocytic glutamate transporter EAAT2 and excitotoxicity [111]. Excitotoxicity was also linked to upregulation of sterol regulatory binding element 1 (SREBP1) in the spinal cords of FALS and SALS patients, and SOD1G93A transgenic mice suggesting cholesterol depletion [115]. Furthermore, the link between ALS and statins, a class of drug which inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, may suggest that suppressing cholesterol synthesis increases the incidence [116, 117], progression, and severity of ALS [118], although this has been questioned [119]. Lipid raft alteration has also been linked to the pathogenesis of ALS. Endogenous, wild-type and mutant SOD1G93A proteins were recruited into lipid rafts isolated from spinal cords of transgenic SOD1 mice [120]. Hence, together the data suggest that oxidative stress may alter sphingolipid and cholesterol metabolism and deregulate lipid raft redox signalling leading to the accumulation of toxic ceramides and cholesterol esters which may ultimately result in motor neuron death [68].

3.5. Mitochondrial Dysfunction

Mitochondria are important players in redox regulation and oxidative stress has the potential to cause mitochondrial dysfunction [70, 121]. Indeed, damaged mitochondria are observed in the spinal cord cells of SALS patients [122124]. The mitochondrial genome is particularly susceptible to oxidative damage [125], hence any increase in cellular ROS would potentially perturb mitochondrial functions. Mitochondria participate in neuronal apoptotic signalling pathways through the release of mitochondrial proteins including cytochrome c into the cytoplasm [126]. There is substantial evidence that molecular components of mitochondrial apoptosis play a role in neurodegeneration in both SOD1 rodents and in mutant SOD1 overexpressed in cell culture [127]. The enzymatic activity of cytochrome c oxidase (COX) in mitochondria is also reduced in the spinal cord cells of SALS patients [122124, 128, 129]. Mitochondria have been well studied in relation to ALS pathogenesis. Degenerating or abnormal mitochondria have been described in mouse models [62, 130], cultured neuronal cellular models [131, 132], and ALS patients [133, 134], although how nonfunctioning mitochondria relate to ALS is unclear. Possible explanations include inhibition of axonal transport, dysregulation of calcium buffering [135], or activation of mitochondrial-dependent apoptosis [128, 136]. Recent studies have shown that overexpression of TDP-43 causes mitochondrial dysfunction and induces mitophagy in cell culture [137]. The presence of ROS and impairment of the mitochondrial respiratory chain have also been observed in TDP-43 models [138, 139].

Mutant SOD1 has also been implicated in mitochondrial respiratory complex impairment [140] and a shift in the redox state of mitochondria towards oxidation [141]. How SOD1 functions in the mitochondria is still not clear, although some data suggests that SOD1 is crucial for maintenance of the mitochondrial redox state [142, 143] and that ALS mutations affect the localisation or function of SOD1 in mitochondria [135]. However, mutant misfolded SOD1 has been found localised with various compartments of the mitochondria [144]. Significantly, any pathological changes in regulation of the electron transport chain would result in more oxidative stress [145] triggering further cellular redox dysregulation, leading to a potential vicious cycle of damage and degeneration.

3.6. Impaired Axonal Transport

Axonal transport is a key mechanism required for cellular viability in neuronal cells. Most proteins required in the axon and in synaptic terminals must be transported along the axon after synthesis in the cell body. Similarly RNA and organelles also need to be transported over long distances, and these transport processes require molecular motors, such as kinesins, dyneins, and myosins that operate along the cellular cytoskeleton. Dysfunction of axonal transport has now been well documented in ALS [61]. Whilst many of these studies implicate dynein in this process [146], several also highlight the importance of kinesin in ALS, particularly kinesin heavy chains KIF5A and KIF1Bβ, which transport mitochondria, synaptic vesicles, and macromolecular complexes. Interestingly, a recent study demonstrated that oxidised wild-type SOD1 immuno-purified from SALS patient tissues inhibited kinesin-based axonal transport in a manner similar to mutant SOD1 in FALS providing evidence for common pathogenic mechanisms in both SALS and FALS [94].

Neurofilaments (NF) accumulation in motor neurons is another histopathological hallmark of ALS [147, 148]. Also, transgenic mice that overexpress NF subunits in motor neurons develop a motor neuron disease with impaired axonal flow, as axonal defects cause delay in transportation of components required for the maintenance of axon [149]. However, ONOO formed during oxidative stress from nitrooxide and superoxide can affect NF assembly and cause NF accumulation in motor neurons [8]. Chou and coworkers showed NF aggregations are associated with SOD1 and nitric oxide synthase activities leading to nitrotyrosine formation on NF [150]. Nitrotyrosine can inhibit phosphorylation of heavy or light NF subunits and may alter axonal transport and trigger motor neuron death [150]. Taken together, these findings suggest a relation between redox regulation and axonal transport dysfunctions in ALS.

3.7. Autophagy

Autophagy is a normal homeostatic mechanism to dispose large protein aggregates, damaged organelles, and long-lived proteins. Autophagic stress results when the number of autophagosomes increases relative to the proportion of degradable proteins. The presence of high levels of superoxide and hydrogen peroxide species can induce autophagy in vitro [151], but consequently, autophagy can further induce oxidative or nitrative stress thus creating a vicious cycle [152]. Dysregulated redox activity also influences autophagy. Cathepsin, a class of proteases which have highly regulated thiol groups [152] and other key regulatory autophagic complexes such as Beclin 1 and Rubicon, also have the presence of cysteine residues [152]. The presence of cysteine residues suggests that they are redox regulated and likely to be affected by ROS. ATG 4, another protease, is a target of oxidation by hydrogen peroxide. However, direct association of these with ALS has not yet been identified. Altered autophagic levels have been observed in SOD1G93A mice and sporadic and familial patients but whether the increased levels are protective or not is still questionable [153156].

3.8. ER Stress and Protein Disulphide Isomerase (PDI) in ALS

The ER is redox regulated and another important location for the production of ROS. It plays key roles in protein and lipid synthesis and protein folding. Protein misfolding within the ER triggers ER stress which induces the unfolded protein response (UPR) a distinct signalling pathway which aims to relieve stress [157]. While initially protective, prolonged UPR causes apoptosis [158, 159]. Recent studies suggest that ER stress is an early and important pathogenic mechanism in ALS [66, 158, 160]. ER stress is induced in animal models of SOD1, in cells expressing mutant FUS and in patients [20, 161]. Oxidative stress driven by changes in fatty acid composition, mitochondrial function, and/or proteosome activity leads to oxidative stress and contributes to ER stress in SALS patients [162, 163]. PDI is an ER chaperone which is induced during UPR and has been implicated in several neurodegenerative disorders including ALS [164166].

PDI is a member of an extended family of foldases and chaperones which are responsible for the formation and isomerisation of protein disulphide bonds [167]. The PDI family comprises 21 members which have structural similarities but different functions [168] and all have a similar active site to thioredoxin [169]. Thioredoxin is an intracellular protein which regulates redox conditions and which is effective against oxidative stress [170]. PDI is most abundant in the ER but it is also found in other subcellular locations such as the nucleus and extracellular matrix [171] and it constitutes 0.8% of the total cellular protein [172]. The yeast PDI crystal structure was recently solved [173] which suggests that and domains are responsible for the formation of disulphide bonds (Figure 1). These domains contain a redox active CGHC motif which isomerases protein disulphide bonds and is involved in redox regulation [173]. PDI also contains and domains which are responsible for substrate binding [174, 175]. Misfolded proteins attach to the hydrophobic region of an inverted U shape structure [173, 176]. The C-terminal region also aids in polypeptide binding and contributes chaperone activity [177]. Compared to other family members, PDI has broad substrate specificities and can interact with glycosylated as well as nonglycosylated proteins [178].

408681.fig.001
Figure 1: Schematic diagram showing domain structure of PDI. Thioredoxin-like domain (orange) and domain (purple) possessing the catalytic motif, catalytically inactive domain (blue), and domain (red). Green represents the linker region which allows flexibility between domains. The C terminal domain is shown in grey followed by the ER retrieval signal KDEL.

4. PDI and Redox Regulation

PDI forms protein disulphide bonds by the oxidation of thiols within the PDI active site cysteine residues [179, 180]. When PDI is in an oxidised state it transfers a disulphide to the substrates thereby oxidising the substrate and becoming reduced itself. Conversely, substrates which need disulphide bond rearrangement are reduced by PDI in the reduced state thus oxidising PDI in the process [168, 181]. This continual cycling regulates redox conditions within the ER. A thiol containing tripeptide protein and glutathione also maintains ER redox homeostasis by similar shuffling between oxidized and reduced cysteine residues. Glutathione is also required for the isomerisation and rearrangement of disulphide bonds [182]. The redox potential of PDI (−110 mV) is lower than other family members [183] due to intervening residues present between the reactive cysteines thus facilitating disulphide bonds [183]. ERO1 oxidises PDI also aiding disulphide bond formations [184], but PDI is also oxidised through peroxiredoxin 4, vitamin K, glutathione peroxidase, and quiescin sulfhydryl oxidase [181]. During ER stress high levels of ERO1 have been observed which accelerates protein oxidation suggesting interplay between oxidative stress and ER stress. The transfer of electrons from the thiol group of PDI to ERO1 results in the production of excess ROS, decreasing the levels of glutathione available for reduction and increasing ERO1 thus altering the redox conditions [185, 186]. Hence, imbalance in the redox state of the ER may result in dysregulation of thiol containing proteins and triggers.

4.1. The Role of PDI in ALS

Due to its function in preventing protein misfolding, PDI is important in protein quality control [166]; also deletion of PDI is embryonically lethal [187]. Hence, regulated expression of PDI is critical for normal cellular function. There is now growing evidence for a role of PDI in ALS. PDI levels are upregulated in transgenic models of ALS and spinal cord tissues of ALS patients [66, 158]. Overexpression of PDI is also protective against mutant SOD1 mediated aggregation and reduces cell death in vitro [20]. PDI coimmunoprecipitates with both SOD1 and FUS [158, 161]; it also colocalises with SOD1, TDP-43, and FUS in ALS patients suggesting a physical interaction exists between PDI and other key misfolded proteins in ALS [66, 161, 188]. Similarly, PDI also colocalises with TDP-43 in ALS tissues and with VAPB inclusions in a Drosophila melanogaster model of ALS [188, 189]. A small mimic of the active site of PDI, dithiol (±)-trans-1,2-bis (mercaptoacetamido) cyclohexane (BMC), is also protective in cell culture and it reduces mutant SOD1 aggregation in a dose dependent manner [20]. Further evidences for a role for disulphide interchange activity in ALS comes from studies showing that another PDI family member ERp57 is also upregulated in transgenic SOD1 mice and ALS patients [66]. Furthermore, thioredoxin is also upregulated in the erythrocytes of FALS patients [19].

The upregulation of these thiol containing proteins in ALS suggests a cellular defensive mechanism is triggered in disease as a defence against oxidative stress. However, there is evidence that normal protective function of PDI is inhibited in disease [20]. Modifications of active site thiol groups through direct oxidation, S-glutathiolation and S-nitrosylation, can lead to inactivation of the normal enzymatic activity of PDI [13, 190, 191]. PDI was recently shown to be S-nitrosylated in ALS [20, 192] as in other neurodegenerative disorders such as Parkinson’s and Alzheimer’s disease. [191]. S-nitrosylation occurs when there is an increased production of RNS during oxidative stress resulting in addition of a nitrogen monoxide group to the thiol side of PDI [20, 164]. Experiments performed by Chen and coworkers suggested that in the presence of S-nitrosylated PDI, the formation of mutant SOD1 aggregates increases in vitro [192]. It is also likely that inactivation of PDI could lead to activation of the UPR as observed in other neurodegenerative disorders [191]. The loss of PDI functional activity can directly lead to apoptosis, or indirectly to a range of cellular abnormalities such as oxidative stress and protein misfolding, which again lead to cell death [164, 166]. Hence the redox regulation of PDI is a crucial component in the maintenance of a balanced redox environment, and inhibition of its enzymatic activity will lead to important consequences for the cell (Figure 2).

408681.fig.002
Figure 2: Redox dysfunction and its relationship to other pathologies in ALS. Alteration in the enzymatic activity of PDI due to redox dysregulation and oxidative stress can further increase the load of misfolded proteins, ER stress, oxidative stress, autophagy, mitochondrial dysfunction, and axonal impairment leading to neuronal cell death.

Neurons are highly susceptible to redox dysregulation due to their high metabolic requirements, large size, and lower ability to maintain the balance between antioxidants and ROS [15]. In disease states such as ALS, oxidative stress, and altered enzymatic activity of PDI, which normally reduces ROS and the burden of misfolded protein, can cause serious damage to the neuron. Since multiple mechanisms are involved in neurodegeneration, any imbalance in redox regulation can lead to an imbalance in the production of free radical species, which consequently cause mitochondrial damage and excitotoxicity, thus elevating the levels of free radicals [193]. Furthermore, an excess of free radicals can also lead to DNA damage and may also result in aggregation of NF [194] and structural destabilization of other proteins, thus inducing ER stress and apoptosis. Since ALS is a slow progressive disorder it could be hypothesised that these cyclic events, due to loss of functional activity of PDI, may gradually lead to neuronal degradation. In such a scenario, the redox regulatory function of PDI may therefore have an important protective effect.

5. Conclusion

Redox regulation is an important mechanism of homeostasis in eukaryotic cells, especially neuronal cells where oxygen levels are high [15]. Many cellular processes rely on it, including proper functioning of the mitochondria and ER, calcium regulation, axonal transport, regulated autophagy, and protein folding. Links between redox dysregulation and ALS are becoming well documented in the literature, although the directionality of these links and their underlying cause are still quite unknown. One possible key player in redox regulation in ALS is PDI, whose role in ALS pathogenesis is the topic of much new research. As the critical protein involved in thiol reduction, any dysregulation of PDI activity can lead to oxidative stress and redox dysregulation. Due to its activity, PDI itself also contains an active site thiol group suggesting that it can also be affected by oxidative stress, leading to an escalating cycle that perpetuates redox dysregulation. How PDI becomes nonfunctional in the first place is still unclear, although some papers point to S-nitrosylation as having a role [20]. Regardless of its exact role, any mechanism to improve the catalytic activity of PDI should have a reductive effect on oxidative stress levels in neurons. It is therefore tempting to speculate about PDI as a possible therapeutic target in the treatment of ALS.

Acknowledgments

This work was supported by the National Health and Medical Research Council of Australia (project Grants 454749, 1006141, and 1030513), Amyotrophic Lateral Sclerosis Association (USA), MND Research Institute of Australia, Bethlehem Griffiths Research Council, Henry H Roth Charitable Foundation Grant for MND Research, Australian Rotary Health, and the Brain Foundation. S. Parakh holds a La Trobe University Post Graduate Research Scholarship.

References

  1. H. Kamata and H. Hirata, “Redox regulation of cellular signalling,” Cellular Signalling, vol. 11, no. 1, pp. 1–14, 1999. View at Publisher · View at Google Scholar · View at Scopus
  2. A. R. Cross and O. T. G. Jones, “Enzymic mechanisms of superoxide production,” Biochimica et Biophysica Acta, vol. 1057, no. 3, pp. 281–298, 1991. View at Scopus
  3. V. Adler, Z. Yin, K. D. Tew, and Z. Ronai, “Role of redox potential and reactive oxygen species in stress signaling,” Oncogene, vol. 18, no. 45, pp. 6104–6111, 1999. View at Scopus
  4. J. Nordberg and E. S. J. Arnér, “Reactive oxygen species, antioxidants, and the mammalian thioredoxin system,” Free Radical Biology and Medicine, vol. 31, no. 11, pp. 1287–1312, 2001. View at Publisher · View at Google Scholar · View at Scopus
  5. M. G. Espey, K. M. Miranda, D. D. Thomas et al., “A chemical perspective on the interplay between NO, reactive oxygen species, and Reactive Nitrogen Oxide Species,” Annals of the New York Academy of Sciences, vol. 962, pp. 195–206, 2002. View at Scopus
  6. W. A. Pryor and G. L. Squadrito, “The chemistry of peroxynitrite: a product from the reaction of nitric oxide with superoxide,” American Journal of Physiology-Lung Cellular and Molecular Physiology, vol. 268, no. 5, pp. L699–L722, 1995. View at Scopus
  7. K. Abe, L. H. Pan, M. Watanabe, H. Konno, T. Kato, and Y. Itoyama, “Upregulation of protein-tyrosine nitration in the anterior horn cells of amyotrophic lateral sclerosis,” Neurological Research, vol. 19, no. 2, pp. 124–128, 1997. View at Scopus
  8. J. S. Beckman, M. Carson, C. D. Smith, and W. H. Koppenol, “ALS, SOD and peroxynitrite,” Nature, vol. 364, no. 6438, p. 584, 1993. View at Publisher · View at Google Scholar · View at Scopus
  9. S. C. Barber and P. J. Shaw, “Oxidative stress in ALS: key role in motor neuron injury and therapeutic target,” Free Radical Biology and Medicine, vol. 48, no. 5, pp. 629–641, 2010. View at Publisher · View at Google Scholar · View at Scopus
  10. M. C. Martínez and R. Andriantsitohaina, “Reactive nitrogen species: molecular mechanisms and potential significance in health and disease,” Antioxidants and Redox Signaling, vol. 11, no. 3, pp. 669–702, 2009. View at Publisher · View at Google Scholar · View at Scopus
  11. D. Trachootham, W. Lu, M. A. Ogasawara, N. R. D. Valle, and P. Huang, “Redox regulation of cell survival,” Antioxidants and Redox Signaling, vol. 10, no. 8, pp. 1343–1374, 2008. View at Publisher · View at Google Scholar · View at Scopus
  12. C. E. Cooper, R. P. Patel, P. S. Brookes, and V. M. Darley-Usmar, “Nanotransducers in cellular redox signaling: modification of thiols by reactive oxygen and nitrogen species,” Trends in Biochemical Sciences, vol. 27, no. 10, pp. 489–492, 2002. View at Publisher · View at Google Scholar · View at Scopus
  13. H. Nakamura, K. Nakamura, and J. Yodoi, “Redox regulation of cellular activation,” Annual Review of Immunology, vol. 15, pp. 351–369, 1997. View at Publisher · View at Google Scholar · View at Scopus
  14. S. A. Lipton, Y. B. Choi, Z. H. Pan et al., “A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds,” Nature, vol. 364, no. 6438, pp. 626–632, 1993. View at Publisher · View at Google Scholar · View at Scopus
  15. B. Halliwell, “Oxidative stress and neurodegeneration: where are we now?” Journal of Neurochemistry, vol. 97, no. 6, pp. 1634–1658, 2006. View at Publisher · View at Google Scholar · View at Scopus
  16. R. P. Guttmann and T. J. Powell, “Redox regulation of cysteine-dependent enzymes in neurodegeneration,” International Journal of Cell Biology, vol. 2012, Article ID 703164, 8 pages, 2012. View at Publisher · View at Google Scholar
  17. H. Tohgi, T. Abe, K. Yamazaki, T. Murata, E. Ishizaki, and C. Isobe, “Increase in oxidized NO products and reduction in oxidized glutathione in cerebrospinal fluid from patients with sporadic form of amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 260, no. 3, pp. 204–206, 1999. View at Publisher · View at Google Scholar · View at Scopus
  18. D. R. Rosen, T. Siddique, D. Patterson et al., “Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis,” Nature, vol. 362, no. 6415, pp. 59–62, 1993. View at Publisher · View at Google Scholar · View at Scopus
  19. Y. Ogawa, H. Kosaka, T. Nakanishi et al., “Stability of mutant superoxide dismutase-1 associated with familial amyotrophic lateral sclerosis determines the manner of copper release and induction of thioredoxin in erythrocytes,” Biochemical and Biophysical Research Communications, vol. 241, no. 2, pp. 251–257, 1997. View at Publisher · View at Google Scholar · View at Scopus
  20. A. K. Walker, M. A. Farg, C. R. Bye, C. A. McLean, M. K. Horne, and J. D. Atkin, “Protein disulphide isomerase protects against protein aggregation and is S-nitrosylated in amyotrophic lateral sclerosis,” Brain, vol. 133, no. 1, pp. 105–116, 2010. View at Publisher · View at Google Scholar · View at Scopus
  21. M. W. Akhtar, C. R. Sunico, T. Nakamura, and S. A. Lipton, “Redox regulation of protein function via cysteine S-nitrosylation and its relevance to neurodegenerative diseases,” International Journal of Cell Biology, vol. 2012, Article ID 463756, 9 pages, 2012. View at Publisher · View at Google Scholar
  22. J. D. Rothstein, “Current hypotheses for the underlying biology of amyotrophic lateral sclerosis,” Annals of Neurology, vol. 65, no. 1, pp. S3–S9, 2009. View at Publisher · View at Google Scholar · View at Scopus
  23. J. Mitchell and G. Borasio, “Amyotrophic lateral sclerosis,” Lancet, vol. 369, no. 9578, pp. 2031–2041, 2007. View at Publisher · View at Google Scholar · View at Scopus
  24. L. C. Wijesekera and P. N. Leigh, “Amyotrophic lateral sclerosis,” Orphanet Journal of Rare Diseases, vol. 4, no. 1, p. 3, 2009. View at Publisher · View at Google Scholar · View at Scopus
  25. G. Bensimon, L. Lacomblez, and V. Meininger, “A controlled trial of riluzole in amyotrophic lateral sclerosis,” New England Journal of Medicine, vol. 330, no. 9, pp. 585–591, 1994. View at Publisher · View at Google Scholar · View at Scopus
  26. R. G. Miller, J. D. Mitchell, M. Lyon, and D. H. Moore, “Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND),” Cochrane Database of Systematic Reviews, no. 1, Article ID CD001447, 2007. View at Publisher · View at Google Scholar · View at Scopus
  27. A. Alonso, G. Logroscino, S. S. Jick, and M. A. Hernán, “Association of smoking with amyotrophic lateral sclerosis risk and survival in men and women: a prospective study,” BMC Neurology, vol. 10, no. 1, p. 6, 2010. View at Publisher · View at Google Scholar · View at Scopus
  28. A. Verma and J. R. Berger, “ALS syndrome in patients with HIV-1 infection,” Journal of the Neurological Sciences, vol. 240, no. 1-2, pp. 59–64, 2006. View at Publisher · View at Google Scholar · View at Scopus
  29. A. Chiò, B. J. Traynor, F. Lombardo et al., “Prevalence of SOD1 mutations in the Italian ALS population,” Neurology, vol. 70, no. 7, pp. 533–537, 2008. View at Publisher · View at Google Scholar · View at Scopus
  30. L. Corrado, R. Del Bo, B. Castellotti et al., “Mutations of FUS gene in sporadic amyotrophic lateral sclerosis,” Journal of Medical Genetics, vol. 47, no. 3, pp. 190–194, 2010. View at Publisher · View at Google Scholar · View at Scopus
  31. J. Sreedharan, I. P. Blair, V. B. Tripathi et al., “TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis,” Science, vol. 319, no. 5870, pp. 1668–1672, 2008. View at Publisher · View at Google Scholar · View at Scopus
  32. E. Pupillo, P. Messina, G. Logroscino et al., “Trauma and amyotrophic lateral sclerosis: a case-control study from a population-based registry,” European Journal of Neurology, vol. 19, no. 12, pp. 1509–1517, 2012. View at Publisher · View at Google Scholar
  33. S. Beretta, M. T. Carrì, E. Beghi, A. Chiò, and C. Ferrarese, “The sinister side of Italian soccer,” Lancet Neurology, vol. 2, no. 11, pp. 656–657, 2003. View at Publisher · View at Google Scholar · View at Scopus
  34. M. R. Turner, C. Wotton, K. Talbot, and M. J. Goldacre, “Cardiovascular fitness as a risk factor for amyotrophic lateral sclerosis: indirect evidence from record linkage study,” Journal of Neurology, Neurosurgery & Psychiatry, vol. 83, pp. 395–398, 2012. View at Publisher · View at Google Scholar
  35. P. A. Dion, H. Daoud, and G. A. Rouleau, “Genetics of motor neuron disorders: new insights into pathogenic mechanisms,” Nature Reviews Genetics, vol. 10, no. 11, pp. 769–782, 2009. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Arai, M. Hasegawa, H. Akiyama et al., “TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis,” Biochemical and Biophysical Research Communications, vol. 351, no. 3, pp. 602–611, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. M. Neumann, D. M. Sampathu, L. K. Kwong et al., “Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis,” Science, vol. 314, no. 5796, pp. 130–133, 2006. View at Publisher · View at Google Scholar · View at Scopus
  38. C. Vance, B. Rogelj, T. Hortobágyi et al., “Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6,” Science, vol. 323, no. 5918, pp. 1208–1211, 2009. View at Publisher · View at Google Scholar · View at Scopus
  39. Y. Yang, A. Hentati, H. X. Deng et al., “The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis,” Nature Genetics, vol. 29, pp. 160–165, 2001. View at Publisher · View at Google Scholar
  40. A. L. Nishimura, M. Mitne-Neto, H. C. A. Silva et al., “A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis,” American Journal of Human Genetics, vol. 75, no. 5, pp. 822–831, 2004. View at Publisher · View at Google Scholar · View at Scopus
  41. T. J. Kwiatkowski Jr., D. A. Bosco, A. L. LeClerc et al., “Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis,” Science, vol. 323, no. 5918, pp. 1205–1208, 2009. View at Publisher · View at Google Scholar · View at Scopus
  42. H. Maruyama, H. Morino, H. Ito et al., “Mutations of optineurin in amyotrophic lateral sclerosis,” Nature, vol. 465, no. 7295, pp. 223–226, 2010. View at Publisher · View at Google Scholar · View at Scopus
  43. H. X. Deng, W. Chen, S. T. Hong et al., “Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia,” Nature, vol. 477, pp. 211–215, 2011. View at Publisher · View at Google Scholar
  44. M. DeJesus-Hernandez, I. R. Mackenzie, B. F. Boeve et al., “Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS,” Neuron, vol. 72, no. 2, pp. 245–256, 2011. View at Publisher · View at Google Scholar
  45. L. I. Bruijn, T. M. Miller, and D. W. Cleveland, “Unraveling the mechanisms involved in motor neuron degeneration in ALS,” Annual Review of Neuroscience, vol. 27, pp. 723–749, 2004. View at Publisher · View at Google Scholar · View at Scopus
  46. H. D. Durham, J. Roy, L. Dong, and D. A. Figlewicz, “Aggregation of mutant Cu/Zn superoxide dismutase proteins in a culture model of ALS,” Journal of Neuropathology and Experimental Neurology, vol. 56, no. 5, pp. 523–530, 1997. View at Scopus
  47. M. Watanabe, M. Dykes-Hoberg, V. Cizewski Culotta, D. L. Price, P. C. Wong, and J. D. Rothstein, “Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues,” Neurobiology of Disease, vol. 8, no. 6, pp. 933–941, 2001. View at Publisher · View at Google Scholar · View at Scopus
  48. C. Soto, “Unfolding the role of protein misfolding in neurodegenerative diseases,” Nature Reviews Neuroscience, vol. 4, no. 1, pp. 49–60, 2003. View at Publisher · View at Google Scholar · View at Scopus
  49. J. Wang, G. Xu, and D. R. Borchelt, “Mapping superoxide dismutase 1 domains of non-native interaction: roles of intra- and intermolecular disulfide bonding in aggregation,” Journal of Neurochemistry, vol. 96, no. 5, pp. 1277–1288, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. B. S. Johnson, D. Snead, J. J. Lee, J. M. McCaffery, J. Shorter, and A. D. Gitler, “TDP-43 is intrinsically aggregation-prone, and amyotrophic lateral sclerosis-linked mutations accelerate aggregation and increase toxicity,” Journal of Biological Chemistry, vol. 284, pp. 20329–20339, 2009. View at Publisher · View at Google Scholar
  51. C. Vance, B. Rogelj, T. Hortobágyi et al., “Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6,” Science, vol. 323, no. 5918, pp. 1208–1211, 2009. View at Publisher · View at Google Scholar · View at Scopus
  52. T. Arai, M. Hasegawa, H. Akiyama et al., “TDP-43 is a component of ubiquitin-positive tau-negative inclusions in frontotemporal lobar degeneration and amyotrophic lateral sclerosis,” Biochemical and Biophysical Research Communications, vol. 351, no. 3, pp. 602–611, 2006. View at Publisher · View at Google Scholar · View at Scopus
  53. N. Shibata, A. Hirano, M. Kobayashi et al., “Intense superoxide dismutase-1 immunoreactivity in intracytoplasmic hyaline inclusions of familial amyotrophic lateral sclerosis with posterior column involvement,” Journal of Neuropathology and Experimental Neurology, vol. 55, no. 4, pp. 481–490, 1996. View at Scopus
  54. J. S. Valentine, P. A. Doucette, and S. Z. Potter, “Copper-zinc superoxide dismutase and amyotrophic lateral sclerosis,” Annual Review of Biochemistry, vol. 74, pp. 563–593, 2005. View at Publisher · View at Google Scholar · View at Scopus
  55. F. Arnesano, L. Banci, I. Bertini, M. Martinelli, Y. Furukawa, and T. V. O'Halloran, “The unusually stable quaternary structure of human Cu,Zn-superoxide dismutase 1 is controlled by both metal occupancy and disulfide status,” Journal of Biological Chemistry, vol. 279, no. 46, pp. 47998–48003, 2004. View at Publisher · View at Google Scholar · View at Scopus
  56. C. Kayatekin, J. A. Zitzewitz, and C. R. Matthews, “Disulfide-Reduced ALS Variants of Cu, Zn Superoxide Dismutase Exhibit Increased Populations of Unfolded Species,” Journal of Molecular Biology, vol. 398, no. 2, pp. 320–331, 2010. View at Publisher · View at Google Scholar · View at Scopus
  57. A. E. Svensson, O. Bilsel, C. Kayatekin, J. A. Adefusika, J. A. Zitzewitz, and C. Robert Matthews, “Metal-free ALS variants of dimeric human Cu,Zn-superoxide dismutase have enhanced populations of monomeric species,” PLoS ONE, vol. 5, no. 4, Article ID e10064, 2010. View at Publisher · View at Google Scholar · View at Scopus
  58. M. Cozzolino, M. G. Pesaresi, V. Gerbino, J. Grosskreutz, and M. T. Carr?, “Amyotrophic lateral sclerosis: new insights into underlying molecular mechanisms and opportunities for therapeutic intervention,” Antioxidants & Redox Signaling, vol. 17, no. 9, pp. 1277–1330, 2012. View at Publisher · View at Google Scholar
  59. O. Spreux-Varoquaux, G. Bensimon, L. Lacomblez et al., “Glutamate levels in cerebrospinal fluid in amyotrophic lateral sclerosis: a reappraisal using a new HPLC method with coulometric detection in a large cohort of patients,” Journal of the Neurological Sciences, vol. 193, no. 2, pp. 73–78, 2002. View at Publisher · View at Google Scholar · View at Scopus
  60. I. Puls, C. Jonnakuty, B. H. LaMonte et al., “Mutant dynactin in motor neuron disease,” Nature Genetics, vol. 33, no. 4, pp. 455–456, 2003. View at Publisher · View at Google Scholar · View at Scopus
  61. J. F. Collard, F. Cote, and J. P. Julien, “Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis,” Nature, vol. 375, no. 6526, pp. 61–64, 1995. View at Scopus
  62. J. Kong and Z. Xu, “Massive mitochondrial degeneration in motor neurons triggers the onset of amyotrophic lateral sclerosis in mice expressing a mutant SOD1,” Journal of Neuroscience, vol. 18, no. 9, pp. 3241–3250, 1998. View at Scopus
  63. F. R. Wiedemann, K. Winkler, A. V. Kuznetsov et al., “Impairment of mitochondrial function in skeletal muscle of patients with amyotrophic lateral sclerosis,” Journal of the Neurological Sciences, vol. 156, no. 1, pp. 65–72, 1998. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Hirano, H. Donnenfeld, S. Sasaki, and I. Nakano, “Fine structural observations of neurofilamentous changes in amyotrophic lateral sclerosis,” Journal of Neuropathology and Experimental Neurology, vol. 43, no. 5, pp. 461–470, 1984. View at Scopus
  65. J. D. Wood, T. P. Beaujeux, and P. J. Shaw, “Protein aggregation in motor neurone disorders,” Neuropathology and Applied Neurobiology, vol. 29, no. 6, pp. 529–545, 2003. View at Publisher · View at Google Scholar · View at Scopus
  66. J. D. Atkin, M. A. Farg, A. K. Walker, C. McLean, D. Tomas, and M. K. Horne, “Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis,” Neurobiology of Disease, vol. 30, no. 3, pp. 400–407, 2008. View at Publisher · View at Google Scholar · View at Scopus
  67. S. Chen, X. Zhang, L. Song, and W. Le, “Autophagy dysregulation in amyotrophic lateral sclerosis,” Brain Pathology, vol. 22, no. 1, pp. 110–116, 2012. View at Publisher · View at Google Scholar
  68. R. G. Cutler, W. A. Pedersen, S. Camandola, J. D. Rothstein, and M. P. Mattson, “Evidence that accumulation of ceramides and cholesterol esters mediates oxidative stress-induced death of motor neurons in amyotrophic lateral sclerosis,” Annals of Neurology, vol. 52, no. 4, pp. 448–457, 2002. View at Publisher · View at Google Scholar · View at Scopus
  69. R. J. Ferrante, S. E. Browne, L. A. Shinobu et al., “Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis,” Journal of Neurochemistry, vol. 69, no. 5, pp. 2064–2074, 1997. View at Scopus
  70. M. Bogdanov, R. H. Brown, W. Matson et al., “Increased oxidative damage to DNA in ALS patients,” Free Radical Biology and Medicine, vol. 29, no. 7, pp. 652–658, 2000. View at Publisher · View at Google Scholar · View at Scopus
  71. A. W. Girotti, “Lipid hydroperoxide generation, turnover, and effector action in biological systems,” Journal of Lipid Research, vol. 39, no. 8, pp. 1529–1542, 1998. View at Scopus
  72. P. J. Shaw, P. G. Ince, G. Falkous, and D. Mantle, “Oxidative damage to protein in sporadic motor neuron disease spinal cord,” Annals of Neurology, vol. 38, no. 4, pp. 691–695, 1995. View at Publisher · View at Google Scholar · View at Scopus
  73. D. Liu, J. Wen, J. Liu, and L. Li, “The roles of free radicals in amyotrophic lateral sclerosis: reactive oxygen species and elevated oxidation of protein, DNA, and membrane phospholipids,” FASEB Journal, vol. 13, no. 15, pp. 2318–2328, 1999. View at Scopus
  74. B. J. Carter, P. Anklesaria, S. Choi, and J. F. Engelhardt, “Redox modifier genes and pathways in amyotrophic lateral sclerosis,” Antioxidants and Redox Signaling, vol. 11, no. 7, pp. 1569–1586, 2009. View at Publisher · View at Google Scholar · View at Scopus
  75. H. F. Poon, K. Hensley, V. Thongboonkerd et al., “Redox proteomics analysis of oxidatively modified proteins in G93A-SOD1 transgenic mice-a model of familial amyotrophic lateral sclerosis,” Free Radical Biology and Medicine, vol. 39, no. 4, pp. 453–462, 2005. View at Publisher · View at Google Scholar · View at Scopus
  76. J. J. Haddad, “Antioxidant and prooxidant mechanisms in the regulation of redox(y)-sensitive transcription factors,” Cellular Signalling, vol. 14, no. 11, pp. 879–897, 2002. View at Publisher · View at Google Scholar · View at Scopus
  77. K. T. Turpaev, “Reactive oxygen species and regulation of gene expression,” Biochemistry, vol. 67, no. 3, pp. 281–292, 2002. View at Publisher · View at Google Scholar · View at Scopus
  78. C. Iaccarino, M. E. Mura, S. Esposito et al., “Bcl2-A1 interacts with pro-caspase-3: implications for amyotrophic lateral sclerosis,” Neurobiology of Disease, vol. 43, no. 3, pp. 642–650, 2011. View at Publisher · View at Google Scholar · View at Scopus
  79. C. Moreau, P. Gosset, J. Kluza et al., “Deregulation of the hypoxia inducible factor-1α pathway in monocytes from sporadic amyotrophic lateral sclerosis patients,” Neuroscience, vol. 172, pp. 110–117, 2011. View at Publisher · View at Google Scholar
  80. C. M. Karch, M. Prudencio, D. D. Winkler, P. J. Hart, and D. R. Borchelt, “Role of mutant SOD1 disulfide oxidation and aggregation in the pathogenesis of familial ALS,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 19, pp. 7774–7779, 2009. View at Publisher · View at Google Scholar · View at Scopus
  81. J. B. Proescher, M. Son, J. L. Elliott, and V. C. Culotta, “Biological effects of CCS in the absence of SOD1 enzyme activation: implications for disease in a mouse model for ALS,” Human Molecular Genetics, vol. 17, no. 12, pp. 1728–1737, 2008. View at Publisher · View at Google Scholar · View at Scopus
  82. J. M. McCord and I. Fridovich, “Superoxide dismutase. An enzymic function for erythrocuprein (hemocuprein),” Journal of Biological Chemistry, vol. 244, no. 22, pp. 6049–6055, 1969. View at Scopus
  83. D. Sau, S. De Biasi, L. Vitellaro-Zuccarello et al., “Mutation of SOD1 in ALS: a gain of a loss of function,” Human Molecular Genetics, vol. 16, no. 13, pp. 1604–1618, 2007. View at Publisher · View at Google Scholar · View at Scopus
  84. J. S. Beckman, M. Carson, C. D. Smith, and W. H. Koppenol, “ALS, SOD and peroxynitrite,” Nature, vol. 364, no. 6438, p. 584, 1993. View at Publisher · View at Google Scholar · View at Scopus
  85. N. V. Blough and O. C. Zafiriou, “Reaction of superoxide with nitric oxide to form peroxonitrite in alkaline aqueous solution,” Inorganic Chemistry, vol. 24, no. 22, pp. 3502–3504, 1985. View at Scopus
  86. M. F. Beal, R. J. Ferrante, S. E. Browne Jr., R. T. Matthews, N. W. Kowall, and R. H. Brown, “Increased 3-nitrotyrosine in both sporadic and familial amyotrophic lateral sclerosis,” Annals of Neurology, vol. 42, no. 4, pp. 644–654, 1997. View at Publisher · View at Google Scholar · View at Scopus
  87. H. Tohgi, T. Abe, K. Yamazaki, T. Murata, E. Ishizaki, and C. Isobe, “Remarkable increase in cerebrospinal fluid 3-nitrotyrosine in patients with sporadic amyotrophic lateral sclerosis,” Annals of Neurology, vol. 46, pp. 129–131, 1999. View at Publisher · View at Google Scholar
  88. F. Casoni, M. Basso, T. Massignan et al., “Protein nitration in a mouse model of familial amyotrophic lateral sclerosis: possible multifunctional role in the pathogenesis,” Journal of Biological Chemistry, vol. 280, no. 16, pp. 16295–16304, 2005. View at Publisher · View at Google Scholar · View at Scopus
  89. S. Guareschi, E. Cova, C. Cereda et al., “An over-oxidized form of superoxide dismutase found in sporadic amyotrophic lateral sclerosis with bulbar onset shares a toxic mechanism with mutant SOD1,” Proceedings of the National Academy of Sciences, vol. 109, no. 13, pp. 5074–5079, 2012. View at Publisher · View at Google Scholar
  90. R. W. Orrell, R. J. M. Lane, and M. Ross, “A systematic review of antioxidant treatment for amyotrophic lateral sclerosis/motor neuron disease,” Amyotrophic Lateral Sclerosis, vol. 9, no. 4, pp. 195–211, 2008. View at Publisher · View at Google Scholar · View at Scopus
  91. S. A. Ezzi, M. Urushitani, and J. P. Julien, “Wild-type superoxide dismutase acquires binding and toxic properties of ALS-linked mutant forms through oxidation,” Journal of Neurochemistry, vol. 102, no. 1, pp. 170–178, 2007. View at Publisher · View at Google Scholar · View at Scopus
  92. R. L. Redler, K. C. Wilcox, E. A. Proctor, L. Fee, M. Caplow, and N. V. Dokholyan, “Glutathionylation at Cys-111 induces dissociation of wild type and FALS mutant SOD1 dimers,” Biochemistry, vol. 50, no. 32, pp. 7057–7066, 2011. View at Publisher · View at Google Scholar
  93. K. Forsberg, P. A. Jonsson, P. M. Andersen et al., “Novel antibodies reveal inclusions containing non-native SOD1 in sporadic ALS patients,” PloS One, vol. 5, no. 7, Article ID e11552, 2010. View at Publisher · View at Google Scholar
  94. D. A. Bosco, G. Morfini, N. M. Karabacak et al., “Wild-type and mutant SOD1 share an aberrant conformation and a common pathogenic pathway in ALS,” Nature Neuroscience, vol. 13, no. 11, pp. 1396–1403, 2010. View at Publisher · View at Google Scholar · View at Scopus
  95. A. C. Estévez, J. P. Crow, J. B. Sampson et al., “Induction of nitric oxide-dependent apoptosis in motor neurons by zinc- deficient superoxide dismutase,” Science, vol. 286, no. 5449, pp. 2498–2500, 1999. View at Publisher · View at Google Scholar · View at Scopus
  96. Y. Furukawa, R. Fu, H. X. Deng, T. Siddique, and T. V. O'Halloran, “Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 18, pp. 7148–7153, 2006. View at Publisher · View at Google Scholar · View at Scopus
  97. T. J. Cohen, A. W. Hwang, T. Unger, J. Q. Trojanowski, and V. M. Y. Lee, “Redox signalling directly regulates TDP-43 via cysteine oxidation and disulphide cross-linking,” The EMBO Journal, vol. 31, no. 5, pp. 1241–1252, 2011. View at Publisher · View at Google Scholar
  98. D. Dormann, R. Rodde, D. Edbauer et al., “ALS-associated fused in sarcoma (FUS) mutations disrupt transportin-mediated nuclear import,” EMBO Journal, vol. 29, no. 16, pp. 2841–2857, 2010. View at Publisher · View at Google Scholar · View at Scopus
  99. S. P. Butcher and A. Hamberger, “In vivo studies on the extracellular, and veratrine-releasable, pools of endogenous amino acids in the rat striatum: effects of corticostriatal deafferentiation and kainic acid lesion,” Journal of Neurochemistry, vol. 48, no. 3, pp. 713–721, 1987. View at Scopus
  100. I. Sen, A. Nalini, N. B. Joshi, and P. G. Joshi, “Cerebrospinal fluid from amyotrophic lateral sclerosis patients preferentially elevates intracellular calcium and toxicity in motor neurons via AMPA/kainate receptor,” Journal of the Neurological Sciences, vol. 235, no. 1-2, pp. 45–54, 2005. View at Publisher · View at Google Scholar · View at Scopus
  101. A. Plaitakis and J. T. Caroscio, “Abnormal glutamate metabolism in amyotrophic lateral sclerosis,” Annals of Neurology, vol. 22, no. 5, pp. 575–579, 1987. View at Scopus
  102. L. Van Den Bosch and W. Robberecht, “Different receptors mediate motor neuron death induced by short and long exposures to excitotoxicity,” Brain Research Bulletin, vol. 53, no. 4, pp. 383–388, 2000. View at Publisher · View at Google Scholar · View at Scopus
  103. D. Trotti, “Neuronal and glial glutamate transporters possess an SH-based redox regulatory mechanism,” European Journal of Neuroscience, vol. 9, no. 6, pp. 1236–1243, 1997. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Plaitakis and E. Constantakakis, “Altered metabolism of excitatory amino acids, N-acetyl-aspartate and N- acetyl-aspartyl-glutamate in amyotrophic lateral sclerosis,” Brain Research Bulletin, vol. 30, no. 3-4, pp. 381–386, 1993. View at Scopus
  105. J. D. Rothstein, L. J. Martin, and R. W. Kuncl, “Decreased glutamate transport by the brain and spinal cord in amyotrophic lateral sclerosis,” New England Journal of Medicine, vol. 326, no. 22, pp. 1464–1468, 1992. View at Scopus
  106. J. D. Rothstein, M. Van Kammen, A. I. Levey, L. J. Martin, and R. W. Kuncl, “Selective loss of glial glutamate transporter GLT-1 amyotrophic lateral sclerosis,” Annals of Neurology, vol. 38, no. 1, pp. 73–84, 1995. View at Publisher · View at Google Scholar · View at Scopus
  107. A. Volterra, D. Trotti, C. Tromba, S. Floridi, and G. Racagni, “Glutamate uptake inhibition by oxygen free radicals in rat cortical astrocytes,” Journal of Neuroscience, vol. 14, no. 5, pp. 2924–2932, 1994. View at Scopus
  108. P. J. Shaw, “Glutamate, excitotoxicity and amyotrophic lateral sclerosis,” Journal of Neurology, vol. 244, no. 2, pp. S3–S14, 1997. View at Scopus
  109. W. L. Miller, “Minireview: regulation of steroidogenesis by electron transfer,” Endocrinology, vol. 146, no. 6, pp. 2544–2550, 2005. View at Publisher · View at Google Scholar · View at Scopus
  110. S. Jin, F. Zhou, F. Katirai, and P. L. Li, “Lipid raft redox signaling: molecular mechanisms in health and disease,” Antioxidants and Redox Signaling, vol. 15, no. 4, pp. 1043–1083, 2011. View at Publisher · View at Google Scholar · View at Scopus
  111. W. A. Pedersen, W. Fu, J. N. Keller et al., “Protein modification by the lipid peroxidation product 4-hydroxynonenal in the spinal cords of amyotrophic lateral sclerosis patients,” Annals of Neurology, vol. 44, no. 5, pp. 819–824, 1998. View at Scopus
  112. L. Dupuis, P. Corcia, A. Fergani et al., “Dyslipidemia is a protective factor in amyotrophic lateral sclerosis,” Neurology, vol. 70, no. 13, pp. 1004–1009, 2008. View at Publisher · View at Google Scholar · View at Scopus
  113. L. Dupuis and J. P. Loeffler, “Neuromuscular junction destruction during amyotrophic lateral sclerosis: insights from transgenic models,” Current Opinion in Pharmacology, vol. 9, no. 3, pp. 341–346, 2009. View at Publisher · View at Google Scholar · View at Scopus
  114. I. Choi, H. D. Song, S. Lee et al., “Direct observation of defects and increased ion permeability of a membrane induced by structurally disordered Cu/Zn-superoxide dismutase aggregates,” PloS One, vol. 6, no. 12, pp. e28982–e28982, 2011. View at Publisher · View at Google Scholar
  115. C. Taghibiglou, J. Lu, I. R. Mackenzie, Y. T. Wang, and N. R. Cashman, “Sterol regulatory element binding protein-1 (SREBP1) activation in motor neurons in excitotoxicity and amyotrophic lateral sclerosis (ALS): indip, a potential therapeutic peptide,” Biochemical and Biophysical Research Communications, vol. 413, no. 2, pp. 159–163, 2011. View at Publisher · View at Google Scholar
  116. E. Colman, A. Szarfman, J. Wyeth et al., “An evaluation of a data mining signal for amyotrophic lateral sclerosis and statins detected in FDA's spontaneous adverse event reporting system,” Pharmacoepidemiology and Drug Safety, vol. 17, no. 11, pp. 1068–1076, 2008. View at Publisher · View at Google Scholar · View at Scopus
  117. I. R. Edwards, K. Star, and A. Kiuru, “Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase,” Drug Safety, vol. 30, no. 6, pp. 515–525, 2007. View at Publisher · View at Google Scholar · View at Scopus
  118. L. Zinman, R. Sadeghi, M. Gawel, D. Patton, and A. Kiss, “Are statin medications safe in patients with ALS?” Amyotrophic Lateral Sclerosis, vol. 9, no. 4, pp. 223–228, 2008. View at Publisher · View at Google Scholar · View at Scopus
  119. H. Toft Sørensen and T. L. Lash, “Statins and amyotrophic lateral sclerosis-the level of evidence for an association,” Journal of Internal Medicine, vol. 266, no. 6, pp. 520–526, 2009. View at Publisher · View at Google Scholar · View at Scopus
  120. J. Zhai, A. L. Ström, R. Kilty et al., “Proteomic characterization of lipid raft proteins in amyotrophic lateral sclerosis mouse spinal cord,” FEBS Journal, vol. 276, no. 12, pp. 3308–3323, 2009. View at Publisher · View at Google Scholar · View at Scopus
  121. M. F. Beal, “Aging, energy, and oxidative stress in neurodegenerative diseases,” Annals of Neurology, vol. 38, no. 3, pp. 357–366, 1995. View at Publisher · View at Google Scholar · View at Scopus
  122. F. R. Wiedemann, G. Manfredi, C. Mawrin, M. Flint Beal, and E. A. Schon, “Mitochondrial DNA and respiratory chain function in spinal cords of ALS patients,” Journal of Neurochemistry, vol. 80, no. 4, pp. 616–625, 2002. View at Publisher · View at Google Scholar · View at Scopus
  123. G. M. Borthwick, M. A. Johnson, P. G. Ince, P. J. Shaw, and D. M. Turnbull, “Mitochondrial enzyme activity in amyotrophic lateral sclerosis: implications for the role of mitochondria in neuronal cell death,” Annals of Neurology, vol. 46, no. 5, pp. 787–790, 2001.
  124. P. M. Keeney and J. P. Bennett, “ALS spinal neurons show varied and reduced mtDNA gene copy numbers and increased mtDNA gene deletions,” Molecular Neurodegeneration, vol. 5, no. 1, p. 21, 2010. View at Publisher · View at Google Scholar · View at Scopus
  125. M. B. Graeber, E. Grasbon-Frodl, U. V. Eitzen, and S. K. Kösel, “Neurodegeneration and aging: role of the second genome,” Journal of Neuroscience Research, vol. 52, no. 1, pp. 1–6, 1998. View at Publisher · View at Google Scholar
  126. K. C. Zimmermann, C. Bonzon, and D. R. Green, “The machinery of programmed cell death,” Pharmacology and Therapeutics, vol. 92, no. 1, pp. 57–70, 2001. View at Publisher · View at Google Scholar · View at Scopus
  127. P. Nagley, G. C. Higgins, J. D. Atkin, and P. M. Beart, “Multifaceted deaths orchestrated by mitochondria in neurones,” Biochimica et Biophysica Acta, vol. 1802, no. 1, pp. 167–185, 2010. View at Publisher · View at Google Scholar · View at Scopus
  128. C. Guégan, M. Vila, G. Rosoklija, A. P. Hays, and S. Przedborski, “Recruitment of the mitochondria-dependent apoptotic pathway in amyotrophic lateral sclerosis,” Journal of Neuroscience, vol. 21, no. 17, pp. 6569–6576, 2001. View at Scopus
  129. L. J. Martin, Z. Liu, K. Chen et al., “Motor neuron degeneration in amyotrophic lateral sclerosis mutant superoxide dismutase-1 transgenic mice: mechanisms of mitochondriopathy and cell death,” Journal of Comparative Neurology, vol. 500, no. 1, pp. 20–46, 2007. View at Publisher · View at Google Scholar · View at Scopus
  130. P. C. Wong, C. A. Pardo, D. R. Borchelt et al., “An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria,” Neuron, vol. 14, no. 6, pp. 1105–1116, 1995. View at Scopus
  131. F. M. Menzies, M. R. Cookson, R. W. Taylor et al., “Mitochondrial dysfunction in a cell culture model of familial amyotrophic lateral sclerosis,” Brain, vol. 125, no. 7, pp. 1522–1533, 2002. View at Scopus
  132. M. T. Carrì, A. Ferri, A. Battistoni et al., “Expression of a Cu,Zn superoxide dismutase typical of familial amyotrophic lateral sclerosis induces mitochondrial alteration and increase of cytosolic Ca2+ concentration in transfected neuroblastoma SH-SY5Y cells,” FEBS Letters, vol. 414, no. 2, pp. 365–368, 1997. View at Publisher · View at Google Scholar · View at Scopus
  133. S. Sasaki and M. Iwata, “Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis,” Neuroscience Letters, vol. 204, no. 1-2, pp. 53–56, 1996. View at Publisher · View at Google Scholar · View at Scopus
  134. L. Siklós, J. Engelhardt, Y. Harati, R. G. Smith, F. Joó, and S. H. Appel, “Ultrastructural evidence for altered calcium in motor nerve terminals in amyotrophic lateral sclerosis,” Annals of Neurology, vol. 39, no. 2, pp. 203–216, 1996. View at Publisher · View at Google Scholar · View at Scopus
  135. M. Cozzolino and M. T. Carrí, “Mitochondrial dysfunction in ALS,” Progress in Neurobiology, vol. 97, no. 2, pp. 54–66, 2012. View at Publisher · View at Google Scholar
  136. K. Y. Soo, J. D. Atkin, M. Farg, A. K. Walker, M. K. Horne, and P. Nagley, “Bim links ER stress and apoptosis in cells expressing mutant SOD1 associated with amyotrophic lateral sclerosis,” PloS One, vol. 7, no. 4, Article ID e35413, 2012.
  137. K. Hong, Y. Li, W. Duan et al., “Full-length TDP-43 and its C-terminal fragments activate mitophagy in NSC34 cell line,” Neuroscience Letters, vol. 530, no. 2, pp. 144–149, 2012. View at Publisher · View at Google Scholar
  138. R. J. Braun and B. Westermann, “Mitochondrial dynamics in yeast cell death and aging,” Biochemical Society Transactions, vol. 39, pp. 1520–1526, 2011. View at Publisher · View at Google Scholar
  139. W. Duan, X. Li, J. Shi, Y. Guo, Z. Li, and C. Li, “Mutant TAR DNA-binding protein-43 induces oxidative injury in motor neuron-like cell,” Neuroscience, vol. 169, no. 4, pp. 1621–1629, 2010. View at Publisher · View at Google Scholar · View at Scopus
  140. C. Jung, C. M. J. Higgins, and Z. Xu, “Mitochondrial electron transport chain complex dysfunction in a transgenic mouse model for amyotrophic lateral sclerosis,” Journal of Neurochemistry, vol. 83, no. 3, pp. 535–545, 2002. View at Publisher · View at Google Scholar · View at Scopus
  141. A. Ferri, M. Cozzolino, C. Crosio et al., “Familial ALS-superoxide dismutases associate with mitochondria and shift their redox potentials,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 37, pp. 13860–13865, 2006. View at Publisher · View at Google Scholar · View at Scopus
  142. K. Aquilano, P. Vigilanza, G. Rotilio, and M. R. Ciriolo, “Mitochondrial damage due to SOD1 deficiency in SH-SY5Y neuroblastoma cells: a rationale for the redundancy of SOD1,” The FASEB Journal, vol. 20, no. 10, pp. 1683–1685, 2006. View at Publisher · View at Google Scholar · View at Scopus
  143. E. M. O'Brien, R. Dirmeier, M. Engle, and R. O. Poyton, “Mitochondrial protein oxidation in yeast mutants lacking manganese- (MnSOD) or copper- and zinc-containing superoxide dismutase (CuZnSOD): evidence that mnsod and cuznsod have both unique and overlapping functions in protecting mitochondrial proteins from oxidative damage,” Journal of Biological Chemistry, vol. 279, no. 50, pp. 51817–51827, 2004. View at Publisher · View at Google Scholar · View at Scopus
  144. S. Pickles and C. V. Velde, “Misfolded SOD1 and ALS: zeroing in on mitochondria,” Amyotrophic Lateral Sclerosis, vol. 13, pp. 333–340, 2012.
  145. B. Bandy and A. J. Davison, “Mitochondrial mutations may increase oxidative stress: implications for carcinogenesis and aging?” Free Radical Biology and Medicine, vol. 8, no. 6, pp. 523–539, 1990. View at Publisher · View at Google Scholar · View at Scopus
  146. F. Zhang, A. L. Ström, K. Fukada, S. Lee, L. J. Hayward, and H. Zhu, “Interaction between familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants and the dynein complex,” Journal of Biological Chemistry, vol. 282, no. 22, pp. 16691–16699, 2007. View at Publisher · View at Google Scholar · View at Scopus
  147. S. Sasaki and S. Maruyama, “Ultrastructutal study of skein-like inclusions in anterior horn neurons of patients with motor neuron disease,” Neuroscience Letters, vol. 147, no. 2, pp. 121–124, 1992. View at Publisher · View at Google Scholar · View at Scopus
  148. D. A. Figlewicz, A. Krizus, M. G. Martinoli et al., “Variants of the heavy neurofilament subunit are associated with the development of amyotrophic lateral sclerosis,” Human Molecular Genetics, vol. 3, no. 10, pp. 1757–1761, 1994. View at Scopus
  149. J. F. Collard, F. Cote, and J. P. Julien, “Defective axonal transport in a transgenic mouse model of amyotrophic lateral sclerosis,” Nature, vol. 375, no. 6526, pp. 61–64, 1995. View at Scopus
  150. S. M. Chou, H. S. Wang, and K. Komai, “Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study,” Journal of Chemical Neuroanatomy, vol. 10, no. 3-4, pp. 249–258, 1996. View at Publisher · View at Google Scholar · View at Scopus
  151. H. Zhang, X. Kong, J. Kang et al., “Oxidative stress induces parallel autophagy and mitochondria dysfunction in human glioma U251 cells,” Toxicological Sciences, vol. 110, no. 2, pp. 376–388, 2009. View at Publisher · View at Google Scholar · View at Scopus
  152. J. Lee, S. Giordano, and J. Zhang, “Autophagy, mitochondria and oxidative stress: cross-talk and redox signalling,” Biochemical Journal, vol. 441, pp. 523–540, 2012. View at Publisher · View at Google Scholar
  153. A. Li, X. Zhang, and W. Le, “Altered macroautophagy in the spinal cord of SOD1 mutant mice,” Autophagy, vol. 4, no. 3, pp. 290–293, 2008. View at Scopus
  154. Y. Zhong, Q. J. Wang, X. Li et al., “Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1-phosphatidylinositol-3-kinase complex,” Nature Cell Biology, vol. 11, no. 4, pp. 468–476, 2009. View at Publisher · View at Google Scholar · View at Scopus
  155. S. Sasaki, “Autophagy in spinal cord motor neurons in sporadic amyotrophic lateral sclerosis,” Journal of Neuropathology and Experimental Neurology, vol. 70, no. 5, pp. 349–359, 2011. View at Publisher · View at Google Scholar · View at Scopus
  156. N. Morimoto, M. Nagai, Y. Ohta et al., “Increased autophagy in transgenic mice with a G93A mutant SOD1 gene,” Brain Research, vol. 1167, no. 1, pp. 112–117, 2007. View at Publisher · View at Google Scholar · View at Scopus
  157. M. Schröder, “Endoplasmic reticulum stress responses,” Cellular and Molecular Life Sciences, vol. 65, no. 6, pp. 862–894, 2008. View at Publisher · View at Google Scholar · View at Scopus
  158. J. D. Atkin, M. A. Farg, B. J. Turner et al., “Induction of the unfolded protein response in familial amyotrophic lateral sclerosis and association of protein-disulfide isomerase with superoxide dismutase 1,” Journal of Biological Chemistry, vol. 281, no. 40, pp. 30152–30165, 2006. View at Publisher · View at Google Scholar · View at Scopus
  159. C. M. Haynes, E. A. Titus, and A. A. Cooper, “Degradation of misfolded proteins prevents ER-derived oxidative stress and cell death,” Molecular Cell, vol. 15, no. 5, pp. 767–776, 2004. View at Publisher · View at Google Scholar · View at Scopus
  160. K. Kanekura, H. Suzuki, S. Aiso, and M. Matsuoka, “ER stress and unfolded protein response in amyotrophic lateral sclerosis,” Molecular Neurobiology, vol. 39, no. 2, pp. 81–89, 2009. View at Publisher · View at Google Scholar · View at Scopus
  161. M. A. Farg, K. Y. Soo, A. K. Walker et al., “Mutant FUS induces endoplasmic reticulum stress in amyotrophic lateral sclerosis and interacts with protein disulfide-isomerase,” Neurobiology of Aging, vol. 33, no. 12, pp. 2855–2868, 2012. View at Publisher · View at Google Scholar
  162. E. V. Ilieva, V. Ayala, M. Jové et al., “Oxidative and endoplasmic reticulum stress interplay in sporadic amyotrophic lateral sclerosis,” Brain, vol. 130, no. 12, pp. 3111–3123, 2007. View at Publisher · View at Google Scholar · View at Scopus
  163. J. D. Malhotra and R. J. Kaufman, “Endoplasmic reticulum stress and oxidative stress: a vicious cycle or a double-edged sword?” Antioxidants and Redox Signaling, vol. 9, no. 12, pp. 2277–2293, 2007. View at Publisher · View at Google Scholar · View at Scopus
  164. A. K. Walker and J. D. Atkin, “Mechanisms of neuroprotection by protein disulphide isomerase in amyotrophic lateral sclerosis,” Neurology Research International, vol. 2011, Article ID 317340, 7 pages, 2011. View at Publisher · View at Google Scholar
  165. R. B. Freedman, T. R. Hirst, and M. F. Tuite, “Protein disulphide isomerase: building bridges in protein folding,” Trends in Biochemical Sciences, vol. 19, no. 8, pp. 331–336, 1994. View at Publisher · View at Google Scholar · View at Scopus
  166. C. I. Andreu, U. Woehlbier, M. Torres, and C. Hetz, “Protein disulfide isomerases in neurodegeneration: from disease mechanisms to biomedical applications,” FEBS Letters, vol. 586, no. 18, pp. 2826–2834, 2012. View at Publisher · View at Google Scholar
  167. J. J. Galligan and D. R. Petersen, “The human protein disulfide isomerase gene family,” Human Genomics, vol. 6, no. 1, pp. 1–15, 2012. View at Publisher · View at Google Scholar
  168. L. Ellgaard and L. W. Ruddock, “The human protein disulphide isomerase family: substrate interactions and functional properties,” EMBO Reports, vol. 6, no. 1, pp. 28–32, 2005. View at Publisher · View at Google Scholar · View at Scopus
  169. B. Wilkinson and H. F. Gilbert, “Protein disulfide isomerase,” Biochimica et Biophysica Acta, vol. 1699, no. 1-2, pp. 35–44, 2004. View at Publisher · View at Google Scholar · View at Scopus
  170. T. Tanaka, H. Nakamura, A. Nishiyama et al., “Redox regulation by thioredoxin superfamily; protection against oxidative stress and aging,” Free Radical Research, vol. 33, no. 6, pp. 851–855, 2000. View at Scopus
  171. C. Turano, S. Coppari, F. Altieri, and A. Ferraro, “Proteins of the PDI family: unpredicted non-ER locations and functions,” Journal of Cellular Physiology, vol. 193, no. 2, pp. 154–163, 2002. View at Publisher · View at Google Scholar · View at Scopus
  172. D. M. Ferrari and H. D. Söling, “The protein disulphide-isomerase family: unravelling a string of folds,” Biochemical Journal, vol. 339, no. 1, pp. 1–10, 1999. View at Publisher · View at Google Scholar · View at Scopus
  173. G. Tian, S. Xiang, R. Noiva, W. J. Lennarz, and H. Schindelin, “The crystal structure of yeast protein disulfide isomerase suggests cooperativity between its active sites,” Cell, vol. 124, no. 1, pp. 61–73, 2006. View at Publisher · View at Google Scholar
  174. P. Klappa, L. W. Ruddock, N. J. Darby, and R. B. Freedman, “The b' domain provides the principal peptide-binding site of protein disulfide isomerase but all domains contribute to binding of misfolded proteins,” EMBO Journal, vol. 17, no. 4, pp. 927–935, 1998. View at Publisher · View at Google Scholar · View at Scopus
  175. A. Pirneskoski, P. Klappa, M. Lobell et al., “Molecular characterization of the principal substrate binding site of the ubiquitous folding catalyst protein disulfide isomerase,” Journal of Biological Chemistry, vol. 279, no. 11, pp. 10374–10381, 2004. View at Publisher · View at Google Scholar · View at Scopus
  176. G. Kozlov, P. Määttänen, D. Y. Thomas, and K. Gehring, “A structural overview of the PDI family of proteins,” FEBS Journal, vol. 277, no. 19, pp. 3924–3936, 2010. View at Publisher · View at Google Scholar · View at Scopus
  177. Y. Dai and C. C. Wang, “A mutant truncated protein disulfide isomerase with no chaperone activity,” Journal of Biological Chemistry, vol. 272, no. 44, pp. 27572–27576, 1997. View at Publisher · View at Google Scholar · View at Scopus
  178. C. E. Jessop, R. H. Watkins, J. J. Simmons, M. Tasab, and N. J. Bulleid, “Protein disulphide isomerase family members show distinct substrate specificity: P5 is targeted to BiP client proteins,” Journal of Cell Science, vol. 122, no. 23, pp. 4287–4295, 2009. View at Publisher · View at Google Scholar · View at Scopus
  179. C. Appenzeller-Herzog, J. Riemer, E. Zito et al., “Disulphide production by Ero1α-PDI relay is rapid and effectively regulated,” EMBO Journal, vol. 29, no. 19, pp. 3318–3329, 2010. View at Publisher · View at Google Scholar · View at Scopus
  180. F. Hatahet and L. W. Ruddock, “Protein disulfide isomerase: a critical evaluation of its function in disulfide bond formation,” Antioxidants and Redox Signaling, vol. 11, no. 11, pp. 2807–2850, 2009. View at Publisher · View at Google Scholar · View at Scopus
  181. N. J. Bulleid and L. Ellgaard, “Multiple ways to make disulfides,” Trends in Biochemical Sciences, 2011. View at Publisher · View at Google Scholar · View at Scopus
  182. S. Chakravarthi, C. E. Jessop, and N. J. Bulleid, “The role of glutathione in disulphide bond formation and endoplasmic-reticulum-generated oxidative stress,” EMBO Reports, vol. 7, no. 3, pp. 271–275, 2006. View at Publisher · View at Google Scholar · View at Scopus
  183. J. Lundström and A. Holmgren, “Determination of the reduction-oxidation potential of the thioredoxin-like domains of protein disulfide-isomerase from the equilibrium with glutathione and thioredoxin,” Biochemistry, vol. 32, no. 26, pp. 6649–6655, 1993. View at Scopus
  184. E. Gross, C. S. Sevier, N. Heldman et al., “Generating disulfides enzymatically: reaction products and electron acceptors of the endoplasmic reticulum thiol oxidase Ero1p,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 2, pp. 299–304, 2006. View at Publisher · View at Google Scholar · View at Scopus
  185. P. I. Merksamer, A. Trusina, and F. R. Papa, “Real-time redox measurements during endoplasmic reticulum stress reveal interlinked protein folding functions,” Cell, vol. 135, no. 5, pp. 933–947, 2008. View at Publisher · View at Google Scholar · View at Scopus
  186. J. W. Cuozzo and C. A. Kaiser, “Competition between glutathione and protein thiols for disulphide-bond formation,” Nature Cell Biology, vol. 1, no. 3, pp. 130–135, 1999. View at Scopus
  187. L. A. Rutkevich, M. F. Cohen-Doyle, U. Brockmeier, and D. B. Williams, “Functional relationship between protein disulfide isomerase family members during the oxidative folding of human secretory proteins,” Molecular Biology of the Cell, vol. 21, no. 18, pp. 3093–3105, 2010. View at Publisher · View at Google Scholar · View at Scopus
  188. Y. Honjo, S. Kaneko, H. Ito et al., “Protein disulfide isomerase-immunopositive inclusions in patients with amyotrophic lateral sclerosis,” Amyotrophic Lateral Sclerosis, vol. 12, no. 6, pp. 444–450, 2011. View at Publisher · View at Google Scholar
  189. H. Tsuda, S. M. Han, Y. Yang et al., “The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors,” Cell, vol. 133, no. 6, pp. 963–977, 2008. View at Publisher · View at Google Scholar · View at Scopus
  190. D. M. Townsend, Y. Manevich, H. Lin et al., “Nitrosative stress-induced S-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response,” Cancer Research, vol. 69, no. 19, pp. 7626–7634, 2009. View at Publisher · View at Google Scholar · View at Scopus
  191. T. Uehara, T. Nakamura, D. Yao et al., “S-Nitrosylated protein-disulphide isomerase links protein misfolding to neurodegeneration,” Nature, vol. 441, no. 7092, pp. 513–517, 2006. View at Publisher · View at Google Scholar · View at Scopus
  192. X. Chen, C. Li, T. Guan et al., “S-nitrosylated protein disulphide isomerase contributes to mutant SOD1 aggregates in amyotrophic lateral sclerosis,” Journal of Neurochemistry, vol. 124, no. 1, pp. 45–58, 2012. View at Publisher · View at Google Scholar
  193. J. D. Rothstein, “Therapeutic horizons for amyotrophic lateral sclerosis,” Current Opinion in Neurobiology, vol. 6, no. 5, pp. 679–687, 1996. View at Publisher · View at Google Scholar · View at Scopus
  194. D. W. Cleveland, “Neuronal growth and death: order and disorder in the axoplasm,” Cell, vol. 84, no. 5, pp. 663–666, 1996. View at Publisher · View at Google Scholar · View at Scopus