ArticleLiterature Review

Oxidative stress and mitochondrial damage in the pathogenesis of ALS: New perspectives

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Abstract

This review attempts to reconcile the present dual view of the mechanisms operating in Amyotrophic Lateral Sclerosis (ALS). On one side, oxidative stress, mitochondrial damage and protein aggregation are considered as causative of the disease, as strongly supported by evidence obtained in models based on the expression of ALS-typical mutant SOD1. On the other hand, evidence from models expressing ALS-typical mutations in RNA-binding proteins such as FUS and TDP43 indicate that mRNA (dys)metabolism is a major pathway in this disease. A critical analysis of existing literature suggests that there may be more than one point of intersection.

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... Stress oxydatif et dysfonction mitochondriale Une des caractéristiques de la SLA est la production excessive et/ou l'échec de la clairance des ROS causant une forte oxydation des protéines, de l'ADN et des lipides dans les tissus des patients atteints de la SLA (Shaw et al. 1995, Shibata et al. 2001, Coppedè 2011, D'Amico et al. 2013). Le stress oxydatif trouvé dans les tissus humains est retrouvé aussi dans les modèles murins (Bozzo et al. 2017) ou dans les cultures cellulaires exprimant des protéines mutées (Duan et al. 2010). Le stress oxydatif présent dans les cellules affectées par la SLA exacerbe le mauvais repliement protéique (Bozzo et al. 2017) notamment en promouvant le potentiel prionique de la protéine SOD1 ou la délocalisation cytoplasmique de TDP43 (Cohen et al. 2015) et de FUS , favorisant la formation de granules de stress par ces deux dernières protéines (Bozzo et al. 2017). ...
... Le stress oxydatif trouvé dans les tissus humains est retrouvé aussi dans les modèles murins (Bozzo et al. 2017) ou dans les cultures cellulaires exprimant des protéines mutées (Duan et al. 2010). Le stress oxydatif présent dans les cellules affectées par la SLA exacerbe le mauvais repliement protéique (Bozzo et al. 2017) notamment en promouvant le potentiel prionique de la protéine SOD1 ou la délocalisation cytoplasmique de TDP43 (Cohen et al. 2015) et de FUS , favorisant la formation de granules de stress par ces deux dernières protéines (Bozzo et al. 2017). Par la phosphorylation oxydative, les mitochondries sont les principales productrices des ROS dans les cellules et sont susceptibles à une dysfonction causée par les protéines associées à la SLA ( Fig.7A) (Bozzo et al. 2017, Greco et al. 2019. ...
... Le stress oxydatif trouvé dans les tissus humains est retrouvé aussi dans les modèles murins (Bozzo et al. 2017) ou dans les cultures cellulaires exprimant des protéines mutées (Duan et al. 2010). Le stress oxydatif présent dans les cellules affectées par la SLA exacerbe le mauvais repliement protéique (Bozzo et al. 2017) notamment en promouvant le potentiel prionique de la protéine SOD1 ou la délocalisation cytoplasmique de TDP43 (Cohen et al. 2015) et de FUS , favorisant la formation de granules de stress par ces deux dernières protéines (Bozzo et al. 2017). Par la phosphorylation oxydative, les mitochondries sont les principales productrices des ROS dans les cellules et sont susceptibles à une dysfonction causée par les protéines associées à la SLA ( Fig.7A) (Bozzo et al. 2017, Greco et al. 2019. ...
... Otherwise, TDP-43 inclusions have been shown to be formed secondary to mitochondrial damage, mediated by caspase and calpain activation [40]. Oxidative stress has been described as a possible cause of TDP-43 aggregation, as inducers of oxidative stress have been demonstrated to delocalise the protein into the cytoplasm, where it then forms aggregates [41]. Interestingly, oxidative stress is known to alter pre-mRNA splicing patterns regulated by TDP-43 [41]. ...
... Oxidative stress has been described as a possible cause of TDP-43 aggregation, as inducers of oxidative stress have been demonstrated to delocalise the protein into the cytoplasm, where it then forms aggregates [41]. Interestingly, oxidative stress is known to alter pre-mRNA splicing patterns regulated by TDP-43 [41]. Furthermore, it has been suggested that the presence of cytoplasmic and intranuclear TDP-43 inclusions may exert neuronal toxicity via a gain of function, or via disruption of physiological functions of TDP-43 in the nucleus, from which it is depleted [42]. ...
... Elevated CSF concentrations of selenium (Se) in the form of selenite ions (SeO 3 2− ), possibly secondary to exposure via drinking water, have been linked to endemic clusters of ALS [6,92]. Iron (Fe) has been observed to accumulate in the brain, spinal cord and CSF of ALS patients [93], who also display elevated blood ferritin concentrations [41,93]. ...
Article
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Amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Parkinson’s disease and similar neurodegenerative disorders take their toll on patients, caregivers and society. A common denominator for these disorders is the accumulation of aggregated proteins in nerve cells, yet the triggers for these aggregation processes are currently unknown. In ALS, protein aggregation has been described for the SOD1, C9orf72, FUS and TDP-43 proteins. The latter is a nuclear protein normally binding to both DNA and RNA, contributing to gene expression and mRNA life cycle regulation. TDP-43 seems to have a specific role in ALS pathogenesis, and ubiquitinated and hyperphosphorylated cytoplasmic inclusions of aggregated TDP-43 are present in nerve cells in almost all sporadic ALS cases. ALS pathology appears to include metal imbalances, and environmental metal exposure is a known risk factor in ALS. However, studies on metal-to-TDP-43 interactions are scarce, even though this protein seems to have the capacity to bind to metals. This review discusses the possible role of metals in TDP-43 aggregation, with respect to ALS pathology.
... F. Xu et al., 2011), as well as mitophagy failure (Lagier-Tourenne et al., 2012a;Polymenidou et al., 2011a;Song, Song, Kincaid, Bossy, & Bossy-Wetzel, 2013). A more detailed description of these mechanisms can be found in (Bozzo, Mirra, & Carrì, 2017). Smith et al., 2017). ...
... R. Li, King, Shorter, & Gitler, 2013), that are formed when cells go under different cellular stress, including oxidative stress. With reports observing prolonged oxidative stress in ALS MNs, partially due to mitochondrial dysfunction, the link can be made between oxidative stress and impaired RNA metabolism through SG formation contributing to FUS aggregation (Bozzo et al., 2017). This is further supported by a study on neuron-like cells where they increased the level of the Oxidative Stress Resistance Protein 1 (Oxr1), a protein essential to protect cells from oxidative stress and shown to bind FUS as well as being up-regulated in spinal cords of ALS patients. ...
... From these results, it has been hypothesized that in pathological conditions, FUS aggregates sequester the chaperones, causing alterations in protein folding control (Bozzo et al., 2017). ...
Thesis
Amyotrophic Lateral Sclerosis (ALS) is a devastating neurodegenerative disorder caused by progressive degeneration of upper and lower motor neurons (MNs), with a very rapid clinical course. It leads to muscle weakness and atrophy progressing to paralysis, with respiratory failure being the major cause of death within years following clinical diagnosis. Two major genes mutated in ALS patients are the RNA-binding protein FUS (FUSed in sarcoma), implicated in RNA metabolism, and coiled-coil-helix-coiled-coil-helix domain 10 (CHCHD10), which plays a role in mitochondria stability. Both these genes have been investigated through different model systems, from small invertebrate models to patient biopsies. However, the major phenotypic features obtained in these models are complex and often controversial. The objective of this work is to provide new insights on the implication of these genes in ALS through the use of new models.To investigate the pathogenic mechanisms induced by FUS and CHCHD10, we generated and characterized two novel stable non-sense mutant zebrafish models for the orthologues of these genes and highlighted several ALS phenotypic features. We demonstrated, for the FUS model but not for CHCHD10, reduced lifespan, locomotor disabilities, aberrant motor axons, disorganized neuromuscular junction (NMJ), muscle and mitochondrial alteration, as well as molecular changes. These findings indicate that loss of fus expression is responsible for the occurrence of distal pathological signs at the NMJ, thus supporting a “dying-back” neuronopathy, in which early disease hallmarks start at the level of the NMJ and progress towards MN cell bodies.
... Oxidative stress is involved in the pathogenesis of ALS and other neurodegenerative disorders. Oxidative stress and its consequent damage to proteins, lipids, DNA and RNA (Blasco et al., 2017;Bozzo et al., 2017) has been extensively reported in ALS animal models (Kraft et al., 2007), fALS patients (Moujalled et al., 2017) and sALS cases (Kato et al., 2005;Kim et al., 2003). Nutritional antioxidants can block neuronal death in vitro and may have therapeutic effects in animal models of neurodegenerative diseases (Esposito et al., 2002). ...
... Oxidative stress mediated protein injury, lipid peroxidation, and DNA and RNA oxidation have been observed in ALS patients; these changes include elevated levels of carbonyl proteins in the spinal cord (Bozzo et al., 2017) and motor cortex (Vargas et al., 2008), increased markers of lipid peroxidation (Esterbauer and Cheeseman, 1990), and higher levels of DNA damage (Bozzo et al., 2017). Oxidative stress biomarkers such as MDA and 8-hydroxy-2 ′ -deoxyguanosine (8-OHdG) are markedly greater (Blasco et al., 2017;Ihara et al., 2005;Oteiza et al., 1997). ...
... Oxidative stress mediated protein injury, lipid peroxidation, and DNA and RNA oxidation have been observed in ALS patients; these changes include elevated levels of carbonyl proteins in the spinal cord (Bozzo et al., 2017) and motor cortex (Vargas et al., 2008), increased markers of lipid peroxidation (Esterbauer and Cheeseman, 1990), and higher levels of DNA damage (Bozzo et al., 2017). Oxidative stress biomarkers such as MDA and 8-hydroxy-2 ′ -deoxyguanosine (8-OHdG) are markedly greater (Blasco et al., 2017;Ihara et al., 2005;Oteiza et al., 1997). ...
Article
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons that results in skeletal muscle atrophy, weakness and paralysis. Oxidative stress plays a key role in the pathogenesis of ALS, including familial forms of the disease arising from mutation of the gene coding for superoxide dismutase (SOD1). We have used the SOD1G93A ALS mouse model to investigate the efficacy of 2-[[(1,1-dimethylethyl)oxidoimino]-methyl]-3,5,6-trimethylpyrazine (TBN), a novel tetramethylpyrazine derivative armed with a powerful free-radical scavenging nitrone moiety. TBN was administered to mice by intraperitoneal or intragastric injection after the onset of motor deficits. TBN slowed the progression of motor neuron disease as evidenced by improved motor performance, reduced spinal motor neuron loss and the associated glial response, and decreased skeletal muscle fiber denervation and fibrosis. TBN treatment activated mitochondrial antioxidant activity through the PGC-1α/Nrf2/HO-1 pathway and decreased the expression of human SOD1. These findings suggest that TBN holds promise as a therapeutic agent for ALS.
... The notion that increased cellular oxidative stress contributes to ALS is supported both by observations from post-mortem ALS tissues, where widespread accumulation of oxidative damage to proteins, lipids, and DNA have been noted [6], and by studies showing that superoxide dismutase (SOD1) mutations are related to increased protein and lipid oxidation [7]. A related putative ALS cause is aggregation of misfolded SOD proteins [8]. ...
... A related putative ALS cause is aggregation of misfolded SOD proteins [8]. Aberrations in chromosome 9 (C9orf72) with nucleotide repeats and hyperphosphorylated tau protein observed in sporadic ALS have also been proposed as potentially causative [9], as has mRNA dysmetabolism [7]. Markers of inflammation are elevated in ALS [10], and the hypothesis that inflammation plays a causative role in ALS is strengthened by observations of activated macrophages and the presence of dendritic cells in ALS spinal cord tissue [11]. ...
... Manganese exposure from food sources has been described to contribute to ALS [7,67,68], yet measurements of Mn exposures in relation to ALS are scarce. Manganese passes barriers between blood and the nervous system [69] and Mn affects mitochondria of ALS nerve cells [70,71] specifically mitochondrial respiratory chain protein function and ATP production [72]. ...
Article
Full-text available
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by motor neuron loss and widespread muscular atrophy. Despite intensive investigations on genetic and environmental factors, the cause of ALS remains unknown. Recent data suggest a role for metal exposures in ALS causation. In this study we present a patient who developed ALS after a traditional medical procedure in Kenya. The procedure involved insertion of a black metal powder into several subcutaneous cuts in the lower back. Four months later, general muscle weakness developed. Clinical and electrophysiological examinations detected widespread denervation consistent with ALS. The patient died from respiratory failure less than a year after the procedure. Scanning electron microscopy and X-ray diffraction analyses identified the black powder as potassium permanganate (KMnO4). A causative relationship between the systemic exposure to KMnO4 and ALS development can be suspected, especially as manganese is a well-known neurotoxicant previously found to be elevated in cerebrospinal fluid from ALS patients. Manganese neurotoxicity and exposure routes conveying this toxicity deserve further attention.
... 61 Oxidative stress has further been linked to the dysregulation and aggregation of key RNA binding proteins that are associated with ALS, such as TDP-43 and FUS. 62 For example, oxidative stress has been shown to cause post-translational modifications, such as cysteine oxidation and acetylation of TDP-43, which both lead to increased aggregation. 63 Additionally, inducers of oxidative stress, such as arsenite and hydrogen peroxide, are routinely used to cause mislocalization of TDP-43 and FUS from the nucleus to the cytoplasm as a method of recapitulating ALS pathology in cellular models. ...
... 67,69 These data suggest that oxidative stress can induce the dysregulation in RNA metabolism seen in ALS; however, there are also data to support the idea that the dysregulation and aggregation of RNA binding proteins in ALS can directly cause damage to DNA and mitochondria, inducing the production of more ROS, and generating a detrimental feed-forward loop accelerating a cycle of oxidative stress, protein aggregation, and mitochondrial dysfunction. 62,70 For example, mutant forms of TDP-43 have been shown to impair mitochondrial structure and dynamics, 43 whereas TDP-43 aggregation induced by oxidative stress was found to cause global mitochondrial dysregulation that further elevated ROS and enhanced TDP-43 aggregation. 71 Historically, the link between ALS and oxidative stress was thought to be limited to SOD1 ALS, but studies in recent years have demonstrated that the impact of oxidative stress on RNA metabolism is relevant to all forms of ALS. ...
Article
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There are no dramatically effective pharmacological treatments for most patients with amyotrophic lateral sclerosis, a complex disease with multiple underlying mechanisms, such as neuroinflammation, oxidative stress, mitochondrial dysfunction, microbiome alteration, and antiretroviral activity. We sifted through 15 years of reviews by a group called ALSUntangled to identify 8 alternative and off‐label treatments that target ≥1 of these mechanisms, and have ≥1 human trial suggesting meaningful benefits. Given the overlapping pathological mechanisms of the highlighted products, we suggest that combinations of these treatments targeting diverse mechanisms might be worthwhile for future amyotrophic lateral sclerosis therapy development. ANN NEUROL 2024
... Oxidative or endoplasmic reticulum (ER) stress elicits a pathological stress response in fus mutant cells. Previous studies implied oxidative stress and ER stress potentially had a role in ALS pathology [26][27][28][29][30][31][32]. Similarly, fus mutant motor neurons did not display qualitative defects when compared to wild-type controls. ...
... Oxidative or endoplasmic reticulum (ER) stress elicits a pathological stress response in fus mutant cells. Previous studies implied oxidative stress and ER stress potentially had a role in ALS pathology [26][27][28][29][30][31][32]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the cyclin F (CCNF) and fused in sarcoma (FUS) genes have been associated with ALS pathology. In this study, we aimed to investigate the functional role of CCNF and FUS in ALS by using genome editing techniques to generate zebrafish models with genetic disruptions in these genes. Sequence comparisons showed significant homology between human and zebrafish CCNF and FUS proteins. We used CRISPR/Cas9 and TALEN-mediated genome editing to generate targeted disruptions in the zebrafish ccnf and fus genes. Ccnf-deficient zebrafish exhibited abnormal motor neuron development and axonal outgrowth, whereas Fus-deficient zebrafish did not exhibit developmental abnormalities or axonopathies in primary motor neurons. However, Fus-deficient zebrafish displayed motor impairments in response to oxidative and endoplasmic reticulum stress. The Ccnf-deficient zebrafish were only sensitized to endoplasmic reticulum stress, indicating that ALS genes have overlapping as well as unique cellular functions. These zebrafish models provide valuable platforms for studying the functional consequences of CCNF and FUS mutations in ALS pathogenesis. Furthermore, these zebrafish models expand the drug screening toolkit used to evaluate possible ALS treatments.
... Low temperature stress will induce a reaction in the enzyme and/or non-enzyme systems of mitochondria to produce excessive ROS, leading to imbalance of oxidation and antioxidant systems [2]. The excessive production of ROS arouses oxidative stress, leading to ultrastructural alterations and causing the loss of cell function and apoptosis [6]. Apoptosis is part of the inflammatory response. ...
... Accumulated evidence suggests that ROS production is closely related to apoptosis [6,31]. Previous reports indicate that low levels of ROS play an important role in cell signal transduction and homeostasis [10]. ...
Article
Temperature is an essential environmental factor for the survival of aquatic animals. Low temperature stress can induce mitochondria to produce excessive ROS and free radicals, and destroy homeostasis. c-Jun N-terminal kinase (JNK) is involved in regulating various physiological processes, including inflammatory responses, cell cycle, reproduction, and apoptosis. Here, we investigated the mechanism of ROS/JNK pathway under low temperature stress both in vitro and in vivo. In this study, transcriptome analysis revealed that apoptosis, autophagy, calcium channel, and antioxidant were involved in the mediation of low temperature tolerance in Pacific white shrimp (penaeus vannamei). PvJNK was activated in response to low temperature stress. Treatments with different temperature caused oxidative stress as demonstrated by increased intensity of the ROS indicator H2DCF-DA, and induced apoptosis as confirmed by indicator FITC. Pretreatment with N-acetylcysteine, an ROS scavenger, attenuated low temperature induced apoptosis, and inhibited the expression of PvJNK. In addition, we demonstrate that mediator PvJNK translocated to nuclear through interacting with PvRheb. By using flow cytometry, inhibiting PvJNK can increase the expression of apoptosis related genes, accelerate tissue damage, and induce ROS and cell apoptosis. The ultimate inhibition of PvJNK accelerates the mortality of shrimp under low temperature stress. Overall, these findings suggest that during low temperature stress, PvJNK was activated by ROS to regulates apoptosis via interacting with PvRheb to promote PvJNK into the nucleus and to improve low temperature tolerance of shrimp.
... Oxidative stress such as increased oxidative species has an essential role in ALS pathology and its increasing in patients can cause disease severity and antioxidants reduction in their blood. The Nrf2-ARE antioxidant pathway induction through compound consumption can slow down disease progress in some mouse models of ALS [65,66]. ...
... Up to the present time, several studies confirm that regimens' treatment can cause motor neuron enhancement (although there are several different descriptions for these improvements). Furthermore, a small pilot trial revealed some advantage of curcumin in PALS [13,65,66,69]. ...
Article
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Progressive abnormality and loss of axons and neurons in the central nervous system (CNS) cause neurodegenerative diseases (NDs). Protein misfolding and its collection are the most important pathological features of NDs. Astrocytes are the most plentiful cells in the mammalian CNS (about 20–40% of the human brain) and have several central functions in the maintenance of the health and correct function of the CNS. Astrocytes have an essential role in the preservation of brain homeostasis, and it is not surprising that these multifunctional cells have been implicated in the onset and progression of several NDs. Thus, they become an exciting target for the study of NDs. Over almost 15 years, it was revealed that curcumin has several therapeutic effects in a wide variety of diseases’ treatment. Curcumin is a valuable ingredient present in turmeric spice and has several essential roles, including those which are anticarcinogenic, hepatoprotective, thrombosuppressive, cardioprotective, anti-arthritic, anti-inflammatory, antioxidant, chemopreventive, chemotherapeutic, and anti-infectious. Furthermore, curcumin can suppress inflammation; promote angiogenesis; and treat diabetes, pulmonary problems, and neurological dysfunction. Here, we review the effects of curcumin on astrocytes in NDs, with a focus on Alzheimer’s disease, Parkinson’s disease, multiple scleroses, Huntington’s disease, and amyotrophic lateral sclerosis.
... Nuclear TDP-43 inhibited FOXO3a, and therefore, enabled the transcription of those genes. Consequently, nuclear depletion of TDP-43 attenuated transcription of mitochondrial genes, culminating in mitochondrial dysfunction [45]. ...
... Cytosolic TDP-43 may also interact with cytosolic chaperones responsible for protein import into mitochondria. Here, mitochondrial damage would occur due to lowering of nuclearencoded mitochondrial protein levels [45]. ...
Article
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In the last decade, pieces of evidence for TDP-43-mediated mitochondrial dysfunction in neurodegenerative diseases have accumulated. In patient samples, in vitro and in vivo models have shown mitochondrial accumulation of TDP-43, concomitantly with hallmarks of mitochondrial destabilization, such as increased production of reactive oxygen species (ROS), reduced level of oxidative phosphorylation (OXPHOS), and mitochondrial membrane permeabilization. Incidences of TDP-43-dependent cell death, which depends on mitochondrial DNA (mtDNA) content, is increased upon ageing. However, the molecular pathways behind mitochondrion-dependent cell death in TDP-43 proteinopathies remained unclear. In this review, we discuss the role of TDP-43 in mitochondria, as well as in mitochondrion-dependent cell death. This review includes the recent discovery of the TDP-43-dependent activation of the innate immunity cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) pathway. Unravelling cell death mechanisms upon TDP-43 accumulation in mitochondria may open up new opportunities in TDP-43 proteinopathy research.
... A number of molecular mechanisms concerning MN degeneration in ALS have been described, among which major topics include glutamate excitotoxicity, structural and functional disorders of mitochondria, impaired axonal functions, protein misfolding linked to endoplasmic reticulum stress, and oxidative stress [6][7][8][9][10]. Also, the involvement of cell types other than MNs in the onset and progression of the disease has been documented, mostly astrocytes, microglia, and oligodendrocytes, leading to the concept of non-cell autonomous pathogenesis [11][12][13]. ...
... The system (1)- (6), which describes the dynamic evolution of the functional agents involved in ALS pathogenesis, can be associated with two signed matrices, as discussed in the "Mathematical model and methods" section. The first is the interaction matrix S, shown in Equation (7), which displays the direct influence of each functional agent on each of the others. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a poor-prognosis disease with puzzling pathogenesis and inconclusive treatments. We develop a mathematical model of ALS based on a system of interactive feedback loops, focusing on the mutant SOD1G93A mouse. Misfolded mutant SOD1 aggregates in motor neuron (MN) mitochondria and triggers a first loop characterized by oxidative phosphorylation impairment, AMP kinase over-activation, 6-phosphofructo-2-kinase (PFK3) rise, glucose metabolism shift from pentose phosphate pathway (PPP) to glycolysis, cell redox unbalance, and further worsening of mitochondrial dysfunction. Oxidative stress then triggers a second loop, involving the excitotoxic glutamatergic cascade, with cytosolic Ca²⁺ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca²⁺ rise is also detrimental to mitochondria and oxidative phosphorylation, thus closing a third loop. These three loops are overlapped and positive (including an even number of inhibitory steps), hence they form a candidate multistationary (bistable) system. To describe the system dynamics, we model the interactions among the functional agents with differential equations. The system turns out to admit two stable equilibria: the healthy state, with high oxidative phosphorylation and preferential PPP, and the pathological state, with AMP kinase activation, PFK3 over expression, oxidative stress, excitotoxicity and MN degeneration. We demonstrate that the loop system is monotone: all functional agents consistently act toward the healthy or pathological condition, depending on low or high mutant SOD1 input. We also highlight that molecular interactions involving PFK3 are crucial, as their deletion disrupts the system’s bistability leading to a single healthy equilibrium point. Hence, our mathematical model unveils that promising ALS management strategies should be targeted to mechanisms that keep low PFK3 expression and activity within MNs.
... Familial ALS (FALS) results from gene mutations, whereas sporadic ALS (sALS) is linked to environmental factors; however, mutational genes also appear in cases of sALS [1]. The pathogenic mechanisms of ALS include excitotoxicity [7], mitochondrial dysfunction, oxidative stress [8], neuroinflammation [9], altered energy metabolism [10], recent RNA misprocessing [11], and other potential pathological changes. Different genes contribute to various pathogenic mechanisms and proportions of patients, as summarized in Table S1 for reference. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative malady that causes progressive degeneration and loss of motor neuron function in the brain and spinal cord, eventually resulting in muscular atrophy, paralysis, and death. Neural stem/progenitor cell (NSPC) transplantation can improve bodily function in animals and delay disease progression in patients with ALS. This paper summarizes and analyzes the efficacy and safety of neural stem/progenitor cell (NSPC) transplantation as a treatment for ALS, aiming to improve function and delay disease progression in patients. We present a summary of the pathogenic mechanism and causative genes associated with ALS and describe the mechanism and efficacy of NSPC treatment for ALS. We comprehensively searched for relevant English-language articles published between January 1, 2000 and October 1, 2023, across the following five medical databases: PubMed, EMBASE, OVID, Web of Science, and the Cochrane Library. We examined experimental indices of physical function in animals and patients who underwent stem cell transplantation. All statistical analyses were performed via Review Manager 5.4. The study comprised a total of 16 investigations, including 5 clinical studies and 11 animal studies and involving 66 patients and 203 animals. The meta-analysis revealed that the administration of NSPCs appeared to yield positive outcomes in clinical patients, as assessed by the ALS functional rating scale and forced vital capacity. Furthermore, improvements following cell injection were observed in the rotarod test results, the Basso-Beattie-Bresnahan Locomotor Rating Scale score, weight, and survival time. Our meta-analysis, which was grounded in randomized controlled trials, revealed that the transplantation of neural stem/progenitor cells (NSPCs), has potential effects on ALS patients, enhancing the physical function of animals and mitigating degenerative effects in individuals. These underscored the promise of NSPC therapy as a viable treatment option. We report that the transplantation of neural stem/progenitor cells (NSPCs) is promising for enhancing bodily function and slowing the progression of ALS in affected patients. In this review, we summarize the treatment of ALS with NSPCs, evaluating both its efficacy and safety. Through database searches, we identified 16 studies involving 66 patients and 203 animals and analyzed the experimental indices of physical function following stem cell transplantation. The meta-analysis results indicated a positive impact of NSPCs on the clinical conditions of patients and the behavior of animals. A meta-analysis of randomized controlled trials further supported the conclusion that NSPC transplantation has a beneficial effect on improving physical function and mitigating degeneration in ALS patients. Graphical Abstract
... Defective mitochondrial respiratory function, a primary source of reactive oxygen species (ROS) production, can lead to elevated intracellular ROS levels. Alleviated ROS and the resulting oxidative stress play a role in the pathogenesis of ALS, potentially leading to the formation of the unfolded protein aggregates that are invariably found in ALS motor neurons [76]. Halter B observed that the accumulation of ROS in skeletal muscles occurs at the asymptomatic stage in SOD1 (G93A) mice [77]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a complex neuromuscular disease characterized by progressive motor neuron degeneration, neuromuscular junction dismantling, and muscle wasting. The pathological and therapeutic studies of ALS have long been neurocentric. However, recent insights have highlighted the significance of peripheral tissue, particularly skeletal muscle, in disease pathology and treatment. This is evidenced by restricted ALS-like muscle atrophy, which can retrogradely induce neuromuscular junction and motor neuron degeneration. Moreover, therapeutics targeting skeletal muscles can effectively decelerate disease progression by modulating muscle satellite cells for muscle repair, suppressing inflammation, and promoting the recovery or regeneration of the neuromuscular junction. This review summarizes and discusses therapeutic strategies targeting skeletal muscles for ALS treatment. It aims to provide a comprehensive reference for the development of novel therapeutics targeting skeletal muscles, potentially ameliorating the progression of ALS.
... Additional RBPs have been suggested to play a role in pathological remodeling through modulation of RNA stability, with much less known about the extent of their mechanisms or functional importance. For example, fused in sarcoma (FUS) is a ubiquitous and versatile protein involved in several cellular processes like DNA repair, gene transcription, oxidative stress, mitochondrial damage and cell apoptosis (Deng et al., 2015;Suzuki and Matsuoka, 2015;Bozzo et al., 2017;Singatulina et al., 2019;Birsa et al., 2020), and has been implicated in regulation of cardiomyocyte apoptosis in myocardial infarction models (Wu et al., 2018). More recently, FUS expression was shown to be induced downstream of AngII in cardiac fibroblasts and play a role in myofibroblast activity, but the mechanism or RNA targets of FUS remain largely unknown . ...
Article
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RNA binding proteins (RBPs) play a central in the post-transcriptional regulation of gene expression, which can account for up to 50% of all variations in protein expression within a cell. Following their binding to target RNAs, RBPs most typically confer changes in gene expression through modulation of alternative spicing, RNA stabilization/degradation, or ribosome loading/translation rate. All of these post-transcriptional regulatory processes have been shown to play a functional role in pathological cardiac remodeling, and a growing body of evidence is beginning to identify the mechanistic contribution of individual RBPs and their cardiac RNA targets. This review highlights the mechanisms of RBP-dependent post-transcriptional gene regulation in cardiomyocytes and fibroblasts and our current understanding of how RNA binding proteins functionally contribute to pathological cardiac remodeling.
... Additionally, alterations in RNA and RNA-binding protein levels, activation of non-neuronal cells such as neuroinflammatory cells (microglia and astroglia) and oligodendroglia, as well as structural and functional alteration of the neuronal cytoskeleton have been reported [20]. Furthermore, oxidative stress and mitochondrial dysfunction have been documented in the pathogenesis of ALS, likely caused by alterations in RNA and RNA-binding proteins (for an in-depth review see [21]). Likewise, dysfunctions in axonal transport [22,23], ubiquitin-proteasome system [24], and nucleocytoplasmic transport [25,26] are observed in the pathogenesis of ALS. ...
Article
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Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as thera- peutic targets in the context of ALS.
... Mutant FUS can cause protein aggregation in the cytoplasm and axoplasm, thereby interfering with organelle trafficking and inducing oxidative stress [43]. Deficient axonal organelle transport in MNs in ALS was described in mutations of C9ORF72, SOD1, TDP-43 and FUS [13,21,44,45]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a devastating motoneuron disease characterized by sustained loss of neuromuscular junctions, degenerating corticospinal motoneurons and rapidly progressing muscle paralysis. Motoneurons have unique features, essentially a highly polarized, lengthy architecture of axons, posing a considerable challenge for maintaining long-range trafficking routes for organelles, cargo, mRNA and secretion with a high energy effort to serve crucial neuronal functions. Impaired intracellular pathways implicated in ALS pathology comprise RNA metabolism, cytoplasmic protein aggregation, cytoskeletal integrity for organelle trafficking and maintenance of mitochondrial morphology and function, cumulatively leading to neurodegeneration. Current drug treatments only have marginal effects on survival, thereby calling for alternative ALS therapies. Exposure to magnetic fields, e.g., transcranial magnetic stimulations (TMS) on the central nervous system (CNS), has been broadly explored over the past 20 years to investigate and improve physical and mental activities through stimulated excitability as well as neuronal plasticity. However, studies of magnetic treatments on the peripheral nervous system are still scarce. Thus, we investigated the therapeutic potential of low frequency alternating current magnetic fields on cultured spinal motoneurons derived from induced pluripotent stem cells of FUS-ALS patients and healthy persons. We report a remarkable restoration induced by magnetic stimulation on axonal trafficking of mitochondria and lysosomes and axonal regenerative sprouting after axotomy in FUS-ALS in vitro without obvious harmful effects on diseased and healthy neurons. These beneficial effects seem to derive from improved microtubule integrity. Thus, our study suggests the therapeutic potential of magnetic stimulations in ALS, which awaits further exploration and validation in future long-term in vivo studies.
... Considering the established connections between mitochondrial dysfunction and disrupted iron homeostasis and a variety of pathologic conditions, including atherosclerosis, type 2 diabetes, neurodegenerative diseases such as Parkinson disease, Alzheimer disease, and amyotrophic lateral sclerosis, and cancer progression and resistance to treatment among others [50][51][52][53][54][55][56][57], it is not surprising that research is uncovering similar connections to the absence or dysfunction of mitoferrins. We will focus here on the consequences associated with dysregulated expression of the mitoferrins in animals ( Table 3), but it is certainly worth mentioning that the dysregulation of the single mitoferrin homolog expressed has also been linked to abnormal growth and development in plants [58][59][60][61]. ...
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Iron is essential for many cellular processes, but cellular iron homeostasis must be maintained to ensure the balance of cellular signaling processes and prevent disease. Iron transport in and out of the cell and cellular organelles is crucial in this regard. The transport of iron into the mitochondria is particularly important, as heme and the majority of iron-sulfur clusters are synthesized in this organelle. Iron is also required for the production of mitochondrial complexes that contain these iron-sulfur clusters and heme. As the principal iron importers in the mitochondria of human cells, the mitoferrins have emerged as critical regulators of cytosolic and mitochondrial iron homeostasis. Here, we review the discovery and structure of the mitoferrins, as well as the significance of these proteins in maintaining cytosolic and mitochondrial iron homeostasis for the prevention of cancer and many other diseases.
... Concerning mitochondrial network, we performed the analysis in 3D, and the presence of a more fragmented network with spheric mitochondria a lower mean volume of the organelle agrees with previous observations reporting a more rounded shape of mitochondria, associated with a fragmented network observed in 2D confocal images. In line with these profound derangements of mitochondrial shape and function, we also observed an increase in the levels of mitochondrial ROS which can contribute to cell damage and ALS onset, as observed for other ALS-causing genes, an in particular SOD1 [33,34]. ...
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Amyotrophic lateral sclerosis is the most common form of motor neuron disease. Mutations in TARDBP, the gene encoding the RNA-binding protein TDP-43, are responsible for about 5% of familial ALS. Here we report the clinical and biological features of an ALS patients with pA382T mutation in TPD-43 protein. Disease began with right hand muscles weakness, and equally involved upper and lower motor neuron with a classic phenotype, without cognitive impairment. While a family history of neurological diseases was reported, there was no evidence of familial frontotemporal dementia. Cultured fibroblasts from the patient were characterized by profound alterations of cell proteome, which impacts particularly the mitochondrial metabolic pathways and the endoplasmic reticulum. TDP-43 levels were similar to control, healthy fibroblasts, but a higher fraction localized in mitochondria. Mitochondrial network appeared fragmented, and the organelles smaller and more spheric. In agreement with impaired proteome and morphology of mitochondria, basal cell respiration was reduced. Mitochondrial DNA levels appeared normal. However, a higher amount of mitochondrial DNA was present in the cytosol, suggesting a pronounced mitochondrial DNA misplacement which can promote a pro-inflammatory response mediating by cGAS/STING. Thus, this case report further expands the clinical and pathological phenotype of A382T mutation.
... AMPK, adenosine monophosphate-activated protein kinase; Bak, B cell lymphoma 2 (Bcl-2) homologous antagonist killer; Bax, Bcl-2-associated X protein; cyt c, cytochrome c; GPx, glutathione peroxidase; HO-1, heme oxygenase-1; IMS, intermembrane space; MAC, mitochondrial apoptosisinduced channel; MCU, mitochondrial calcium uniporter; Mn-SOD (SOD2), manganese superoxide dismutase; MOMP, mitochondrial outer membrane permeabilization; mPTP, mitochondrial permeability transition pore; mtDNA, mitochondrial DNA; mTOR, mechanistic (or mammalian) target of rapamycin; NCLX, the mitochondrial Na/Li/Ca exchanger; Nrf1/2, nuclear respiratory factor 1 and 2; O2 •−, superoxide radical; OXPHOS, oxidative phosphorylation; PGC-1α, peroxisome proliferator-activated receptor coactivator-1α; PRx, peroxiredoxins (scavenger and antioxidant) ROS, reactive oxidative species; SIRT-1, sirtuin 1; SOD1/2, superoxide dismutase; TFAM, mitochondrial transcription factor A; ULK1, Unc-51 like kinase 1; VDAC, voltage-dependent anion-selective channel; α-syn, α-synuclein. Bozzo et al., 2017;Carrì et al., 2017) and utilization of mitochondrial protective agents like RES can be a favorable approach for restoring the function and dynamics of mitochondria resulting in improvements in different cellular aspects such as bioenergetic and redox status in patient with ALS. ...
Article
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Most polyphenols can cross blood-brain barrier, therefore, they are widely utilized in the treatment of various neurodegenerative diseases (ND). Resveratrol, a natural polyphenol contained in blueberry, grapes, mulberry, etc., is well documented to exhibit potent neuroprotective activity against different ND by mitochondria modulation approach. Mitochondrial function impairment is the most common etiology and pathological process in various neurodegenerative disorders, viz. Alzheimer’s disease, Parkinson’s disease, Huntington’s disease and amyotrophic lateral sclerosis. Nowadays these ND associated with mitochondrial dysfunction have become a major threat to public health as well as health care systems in terms of financial burden. Currently available therapies for ND are limited to symptomatic cures and have inevitable toxic effects. Therefore, there is a strict requirement for a safe and highly effective drug treatment developed from natural compounds. The current review provides updated information about the potential of resveratrol to target mitochondria in the treatment of ND.
... Mitochondrial dysfunction and oxidative stress are directly interlinked where inefficient mitochondrial oxidative phosphorylation causes the accumulation of reactive oxygen species (ROS) that causes oxidative stress by damaging intracellular DNA, lipids, and proteins, leading to necrosis and apoptotic cell death [122]. In this context, unfolded protein aggregates formed by oxidative stress lead to the activation of autophagy [123] where autophagy plays a protective role to limit the damage from ROS [63]. To benefit cell survival, induced autophagy degrades aggregates of damaged mitochondria and reduces ROS-induced damage, subsequently preventing cell death [63,124]. ...
Article
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Amyotrophic lateral sclerosis (ALS) patients show a myriad of energetic abnormalities, such as weight loss, hypermetabolism, and dyslipidaemia. Evidence suggests that these indices correlate with and ultimately affect the duration of survival. This review aims to discuss ALS metabolic abnormalities in the context of autophagy, the primordial system acting at the cellular level for energy production during nutrient deficiency. As the primary pathway of protein degradation in eukaryotic cells, the fundamental role of cellular autophagy is the adaptation to metabolic demands. Therefore, autophagy is tightly coupled to cellular metabolism. We review evidence that the delicate balance between autophagy and metabolism is aberrant in ALS, giving rise to intracellular and systemic pathophysiology observations. Understanding the metabolism autophagy crosstalk can lead to the identification of novel therapeutic targets for ALS.
... In addition, CL peroxidation was increased in the spinal cord and brain of the SOD1 G93A transgenic mice, which is accompanied by impaired mitochondrial oxidative phosphorylation activity and increased cytochrome c release, a leading indicator of apoptosis [31]. These alterations in CL are consistent with the loss of mitochondrial integrity observed in several models of ALS [32]. However, the underlying causes of aberrant CL metabolism in ALS remain elusive. ...
Article
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Objective Mutations in the copper-zinc superoxide dismutase (SOD1) gene cause familial amyotrophic lateral sclerosis (ALS), a progressive fatal neuromuscular disease characterized by motor neurons death and severe skeletal muscle degeneration. However, there is no effective treatment for this debilitating disease, since the underlying cause for the pathogenesis remains poorly understood. Here, we investigated a role of acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1), an acyltransferase that promotes mitochondrial dysfunction in age-related diseases by catalyzing pathological remodeling of cardiolipin, in promoting the development of ALS in the SOD1G93A transgenic mice. Methods Using SOD1G93A transgenic mice with targeted deletion of the ALCAT1 gene and treated with Dafaglitapin (Dafa), a very potent and highly selective ALCAT1 inhibitor, we determined whether ablation or pharmaceutical inhibition of ALCAT1 by Dafa would mitigate ALS and the underlying pathogenesis by preventing pathological remodeling of cardiolipin, oxidative stress, and mitochondrial dysfunction by multiple approaches, including lifespan analysis, behavioral tests, morphological and functional analysis of skeletal muscle, electron microscopic and Seahorse analysis of mitochondrial morphology and respiration, western blot analysis of the SOD1G93A protein aggregation, and lipidomic analysis of cardiolipin content and acyl composition in mice spinal cord. Results ALCAT1 protein expression is potently upregulated in the skeletal muscle of the SOD1G93A mice. Consequently, ablation or pharmacological inhibition of ALCAT1 by Dafa attenuates motor neuron dysfunction, neuronal inflammation, and skeletal muscle atrophy in SOD1G93A mice by preventing SOD1G93A protein aggregation, mitochondrial dysfunction, and pathological CL remodeling, leading to moderate extension of lifespan in the SOD1G93A transgenic mice. Conclusion ALCAT1 promotes the development of ALS by linking SOD1G93A protein aggregation to mitochondrial dysfunction, implicating Dafa as a potential treatment for this debilitating disorder.
... Fe load was evident in the spinal cord of ALS patients [121], the motor cortex of ALS patients [122], gray matter from the frontal cortex of ALS patients [123], in the serum of ALS patients [124], and the CSF of ALS patients [125]. Recent evidence has shown that oxidative burst due to Fenton chemistry is implicated in the pathology of ALS [116,[126][127][128]. ...
Article
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Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.
... Of the main process arising from the MTHFR gene polymorphism liked to HHcy, oxidative stress presents itself as a mechanism implicated in many intracellular alterations in ALS neurodegeneration [97]. In the transsulfuration pathway, Hcy is converted to cystathionine and later to cysteine, the precursor molecule in protein and glutathione (GSH) synthesis. ...
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Amyotrophic Lateral Sclerosis (ALS) is a progressive and lethal neurodegenerative disease without a definitive diagnostic test and effective treatment. A plethora of studies suggest that genetic factors play an important role in ALS development, and potentially link folate pathway dysregulation to disease pathogenesis. This study aims to evaluate folate dysregulation due to MTHFR C677T polymorphism and other factors such as sociodemographic and clinical, to better elucidate the involvement of these factors in ALS pathogenesis, and to investigate possible biomarkers for use as disease diagnostics or prognostics. This hospital-based case-control study analyzed 101 patients diagnosed with ALS and 119 considered healthy, with no suspicion or diagnosis of neurodegenerative disease. Blood samples were collected, stored, and underwent DNA extraction. Clinical and sociodemographic data from patients were collected through a questionnaire, as well as consultation of medical records. Genotypic analyses were performed using PCR-RFLP, and statistical analysis of clinical and genotypic data was conducted with SPSS software, version 23. The results show a higher presence of the mutant genotype (p = 0.02) in the case group, and suggest that mutant allele (T) is a risk factor for ALS susceptibility (OR = 1.54; 95% CI = 1.05–2.29; p = 0.03). Mutant genotype (T/T) interacts with both demographics (White p = 0.005 / Brown p = 0,001) and clinical factors (Physical activity p = 0.006) as risk factors for ALS. Also, a significant difference in alcohol consumption (p = 0.001) between the case and control group was observed. Moreover, a statistical trend towards faster disease progression and death was observed for patients with the mutant allele (T) (p = 0.06). Thus, the results of this study suggest that folate deficiency due to MTHFR C677T polymorphism is implicated in ALS through pathogenic mechanisms and interaction with other risk factors, resulting in faster disease progression and early death.
... [17][18][19][20][21][22] There is also a strong causal relationship between the presence of chronic oxidative stress and the development of mitochondrial damage and bioenergetic failure, especially in the context of aging, neurodegenerative disease, and neuropsychiatric illness. 23,[33][34][35][36][37] Perturbations in redox homeostasis are also seen in numerous disease models of psychiatric illness. [30][31][32] Indeed, the DISC1 gene, which has been shown to influence endophenotypes associated with psychiatric disease and has spurred the generation of numerous murine and rat animal models targeting this gene, plays a critical role in mitochondrial homeostasis and transport, metabolic function of astrocytes, and modulation of endoplasmic reticulum-mitochondria dynamics. ...
Article
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Purpose Oxidative stress and downstream effectors have emerged as important pathological processes that drive psychiatric illness, suggesting that antioxidants may have a therapeutic role in psychiatric disease. However, no imaging biomarkers are currently available to track therapeutic response. The purpose of this study was to examine whether advanced DWI techniques are able to sensitively detect the potential therapeutic effects of the antioxidant N‐acetylcysteine (NAC) in a Disc1 svΔ2 preclinical rat model of psychiatric illness. Methods Male and female Disc1 svΔ2 rats and age‐matched, sex‐matched Sprague‐Dawley wild‐type controls were treated with a saline vehicle or NAC before ex vivo MRI acquisition at P50. Imaging data were fit to DTI and neurite orientation dispersion and density imaging models and analyzed for region‐specific changes in quantitative diffusion metrics. Brains were further processed for cellular quantification of microglial density and morphology. All experiments were repeated for Disc1 svΔ2 rats exposed to chronic early‐life stress to test how gene‐environment interactions might alter effectiveness of NAC therapy. Results The DTI and neurite orientation dispersion and density imaging analyses demonstrated amelioration of early‐life, sex‐specific neural microstructural deficits with concomitant differences in microglial morphology across multiple brain regions relevant to neuropsychiatric illness with NAC treatment, but only in male Disc1 svΔ2 rats. Addition of chronic early‐life stress reduced the ability of NAC to restore microstructural deficits. Conclusion These findings provide evidence for a treatment pathway targeting endogenous antioxidant capacity, and the clinical translational utility of neurite orientation dispersion and density imaging microstructural imaging to sensitively detect microstructural alterations resulting from antioxidant treatment.
... Oxidative stress and RNA metabolism are considered to be the pathogenesis of ALS, and there is increasing evidence of the relationship between these two aspects. Oxidative stress causes abnormalities in RNA metabolism, and conversely, abnormalities in RNA metabolism cause oxidative stress [128]. Indeed, increased oxidative RNA modification and alteration of splicing and expression of mRNA are recognized in the spinal motor neurons of SOD-1 mutant mice [129,130]. ...
Article
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Reduction–oxidation reactions are essential to cellular homeostasis. Oxidative stress transcends physiological antioxidative system damage to biomolecules, including nucleic acids and proteins, and modifies their structures. Amyotrophic lateral sclerosis (ALS) is the most common adult-onset motor neuron disease. The cells present in the central nervous system, including motor neurons, are vulnerable to oxidative stress. Neurodegeneration has been demonstrated to be caused by oxidative biomolecular modifications. Oxidative stress has been suggested to be involved in the pathogenesis of ALS. Recent progress in research on the underlying mechanisms of oxidative stress in ALS has led to the development of disease-modifying therapies, including edaravone. However, the clinical effects of edaravone remain limited, and ALS is a heretofore incurable disease. The reason for the lack of reliable biomarkers and the precise underlying mechanisms between oxidative stress and ALS remain unclear. As extracellular proteins and RNAs present in body fluids and represent intracellular pathological neurodegenerative processes, extracellular proteins and/or RNAs are predicted to promise diagnosis, prediction of disease course, and therapeutic biomarkers for ALS. Therefore, we aimed to elucidate the underlying mechanisms between oxidative stress and ALS, and promising biomarkers indicating the mechanism to determine whether therapy targeting oxidative stress can be fundamental for ALS.
... Much of the current literature postulates that UA plays an important role in ameliorating oxidative stress, and research has focused on addressing UA-induced neuroprotective effects. Authors often suggest that UA produced from inosine via xanthine [105] may provide some level of neuroprotection, partly based on an antioxidant action [106,107], since oxidative stress is thought to induce motor neuron death and promote the pathogenesis of ALS [108][109][110]. Additionally, UA-induced protection of spinal cord neurons from glutamatergic excitotoxicity via astrocytes has also been proposed as another possible mechanism [111]. ...
Article
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Adenosine is extensively distributed in the central and peripheral nervous systems, where it plays a key role as a neuromodulator. It has long been implicated in the pathogenesis of progressive neurogenerative disorders such as Parkinson’s disease, and there is now growing interest in its role in amyotrophic lateral sclerosis (ALS). The motor neurons affected in ALS are responsive to adenosine receptor function, and there is accumulating evidence for beneficial effects of adenosine A2A receptor antagonism. In this article, we focus on recent evidence from ALS clinical pathology and animal models that support dynamism of the adenosinergic system (including changes in adenosine levels and receptor changes) in ALS. We review the possible mechanisms of chronic neurodegeneration via the adenosinergic system, potential biomarkers and the acute symptomatic pharmacology, including respiratory motor neuron control, of A2A receptor antagonism to explore the potential of the A2A receptor as target for ALS therapy.
... Rather, gain of function effects dominate for mutant proteins and result in the aggregation of SOD1 clusters within astrocytes or motor neurons [39,40]. In these cell types, SOD1 aggregates are found in the cytosol, but also within mitochondria, thus creating oxidative stress [41,42]. Other ALS gene products have been identified that produce proteins controlling mitochondrial protein import (coiled-coil-helix-coiled-coil domain protein 10, CHCHD10, [43]), the cytoskeleton (e.g., Profilin-1, ALS18), mRNA stability (e.g., Fused in sarcoma, FUS, ALS6), and protein trafficking (e.g., valosin-containing protein, VCP, ALS14) [44,45]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease for which there is currently no cure. Progress in the characterization of other neurodegenerative mechanisms has shifted the spotlight onto an intracellular structure called mitochondria-endoplasmic reticulum (ER) contacts (MERCs) whose ER portion can be biochemically isolated as mitochondria-associated membranes (MAMs). Within the central nervous system (CNS), these structures control the metabolic output of mitochondria and keep sources of oxidative stress in check via autophagy. The most relevant MERC controllers in the ALS pathogenesis are vesicle-associated membrane protein-associated protein B (VAPB), a mitochondria-ER tether, and the ubiquitin-specific chaperone valosin containing protein (VCP). These two systems cooperate to maintain mitochondrial energy output and prevent oxidative stress. In ALS, mutant VAPB and VCP take a central position in the pathology through MERC dysfunction that ultimately alters or compromises mitochondrial bioenergetics. Intriguingly, both proteins are targets themselves of other ALS mutant proteins, including C9orf72, FUS, or TDP-43. Thus, a new picture emerges, where different triggers cause MERC dysfunction in ALS, subsequently leading to well-known pathological changes including endoplasmic reticulum (ER) stress, inflammation, and motor neuron death.
... A reduction in mitochondrial complex I activity and mitochondrial DNA perturbation were corroborated in studies of muscles in sporadic ALS patients 18,19 . These data suggest a role for mitochondrial dysfunction in ALS etiology, as reviewed in many recent publications 1,11,[20][21][22] . Oxaloacetate plays a role in cell bioenergetics, and its administration affects bioenergetics-relevant infrastructure. ...
Article
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Amyotrophic lateral sclerosis (ALS) remains a devastating motor neuron disease with limited treatment options. Oxaloacetate treatment has a neuroprotective effect in rodent models of seizure and neurodegeneration. Therefore, we treated the ALS model superoxide dismutase 1 (SOD1) G93A mice with oxaloacetate and evaluated their neuromuscular function and lifespan. Treatment with oxaloacetate beginning in the presymptomatic stage significantly improved neuromuscular strength measured during the symptomatic stage in the injected mice compared to the non-treated group. Oxaloacetate treatment starting in the symptomatic stage significantly delayed limb paralysis compared with the non-treated group. For lifespan analysis, oxaloacetate treatment did not show a statistically significant positive effect, but the treatment did not shorten the lifespan. Mechanistically, SOD1 G93A mice showed increased levels of tumor necrosis factor-α (TNFα) and peroxisome proliferative activated receptor gamma coactivator 1α (PGC-1α) mRNAs in the spinal cord. However, oxaloacetate treatment reverted these abnormal levels to that of wild-type mice. Similarly, the altered expression level of total NF-κB protein returned to that of wild-type mice with oxaloacetate treatment. These results suggest that the beneficial effects of oxaloacetate treatment in SOD1 G93A mice may reflect the effects on neuroinflammation or bioenergetic stress.
... In the early stages of HD, RNA oxidation might be associated with the transcription and translation of the CAG repeat of the HTT gene, leading to neuronal dysfunction and striatum cell death [100]. In the process of ALS development, RNA oxidation may change the structure of proteins, driving to abnormal protein aggregates in the cytoplasm that promote the development of the disease [101,102]. In addition, RNA damage has been also linked to the occurrence and evolution of a variety of other chronic diseases such as atherosclerosis, type 2 diabetes, and cancers [2]. ...
Article
Interest in RNA damage as a novel threat associated with several human pathologies is rapidly increasing. Knowledge on damaged RNA recognition, repair, processing and decay is still scanty. Interestingly, in the last few years, more and more evidence put a bridge between DNA damage repair enzymes and the RNA world. The Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) was firstly identified as a crucial enzyme of the base excision repair (BER) pathway preserving genome stability toward non-distorting DNA lesion-induced damages. Later, an unsuspected role of APE1 in controlling gene expression was discovered and its pivotal involvement in several human pathologies, ranging from tumor progression to neurodegenerative diseases, has emerged. Recent novel findings indicate a role of APE1 in RNA metabolism, particularly in processing activities of damaged (abasic and oxidized) RNA and in the regulation of oncogenic microRNAs (miRNAs). Even though the role of miRNAs in human pathologies is well-known, the mechanisms underlying their quality control are still totally unexplored. A detailed knowledge of damaged RNA decay processes in human cells is crucial in order to understand the molecular processes involved in multiple pathologies. This cutting-edge perspective article will highlight these emerging aspects of damaged RNA processing and decay, focusing the attention on the involvement of APE1 in RNA world.
... Additional studies on ALS also demonstrate alterations in markers of oxidative stress, such as glutathione and nuclear factor E2-related factor-2 [56][57][58]. Furthermore, post-mortem results in both sALS and fALS patients reveal DNA, lipid and protein damage secondary to oxidative stress [59][60][61][62][63]. Together, this evidence reinforces the likelihood that CS-mediated oxidative stress is a key driver of ALS pathogenesis. ...
Article
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Cigarette smoke (CS) has been consistently demonstrated to be an environmental risk factor for amyotrophic lateral sclerosis (ALS), although the molecular pathogenic mechanisms involved are yet to be elucidated. Here, we propose different mechanisms by which CS exposure can cause sporadic ALS pathogenesis. Oxidative stress and neuroinflammation are widely implicated in ALS pathogenesis, with blood–spinal cord barrier disruption also recognised to be involved in the disease process. In addition, immunometabolic, epigenetic and microbiome alterations have been implicated in ALS recently. Identification of the underlying pathophysiological mechanisms that underpin CS-associated ALS will drive future research to be conducted into new targets for treatment.
... In summary, it is generally still unclear whether oxidative stress and mitochondrial damage occur at the beginning of these pathological processes and then cause the impairment of RNA metabolism or if disordered RNA metabolism causes mitochondrial damage and oxidative stress is generally unclear [80]. In support of the first hypothesis, findings suggest that both the TDP-43 and FUS proteins tend to translocate to the cytoplasm to form inclusions upon exposure to excessive oxidative stress [81,82]. ...
Article
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Amyotrophic lateral sclerosis (ALS) affects motor neurons in the cerebral cortex, brainstem and spinal cord and leads to death due to respiratory failure within three to five years. Although the clinical symptoms of this disease were first described in 1869 and it is the most common motor neuron disease and the most common neurodegenerative disease in middle-aged individuals, the exact etiopathogenesis of ALS remains unclear and it remains incurable. However, free oxygen radicals (i.e., molecules containing one or more free electrons) are known to contribute to the pathogenesis of this disease as they very readily bind intracellular structures, leading to functional impairment. Antioxidant enzymes, which are often metalloenzymes, inactivate free oxygen radicals by converting them into a less harmful substance. One of the most important antioxidant enzymes is Cu2+Zn2+ superoxide dismutase (SOD1), which is mutated in 20% of cases of the familial form of ALS (fALS) and up to 7% of sporadic ALS (sALS) cases. In addition, the proper functioning of catalase and glutathione peroxidase (GPx) is essential for antioxidant protection. In this review article, we focus on the mechanisms through which these enzymes are involved in the antioxidant response to oxidative stress and thus the pathogenesis of ALS and their potential as therapeutic targets.
... Oxidizing species may damage lipids, nucleic acids, and proteins and thus are potentially toxic to cells and energy production at several levels. Because most molecular oxygen is utilized by mitochondria for ETC activity (and is reduced to water), mitochondria are particularly susceptible to OS. OS damage has been described in ALS [74,75] ...
Article
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Adult human brains consume a disproportionate amount of energy substrates (2–3% of body weight; 20–25% of total glucose and oxygen). Adenosine triphosphate (ATP) is a universal energy currency in brains and is produced by oxidative phosphorylation (OXPHOS) using ATP synthase, a nano-rotor powered by the proton gradient generated from proton-coupled electron transfer (PCET) in the multi-complex electron transport chain (ETC). ETC catalysis rates are reduced in brains from humans with neurodegenerative diseases (NDDs). Declines of ETC function in NDDs may result from combinations of nitrative stress (NS)–oxidative stress (OS) damage; mitochondrial and/or nuclear genomic mutations of ETC/OXPHOS genes; epigenetic modifications of ETC/OXPHOS genes; or defects in importation or assembly of ETC/OXPHOS proteins or complexes, respectively; or alterations in mitochondrial dynamics (fusion, fission, mitophagy). Substantial free energy is gained by direct O2-mediated oxidation of NADH. Traditional ETC mechanisms require separation between O2 and electrons flowing from NADH/FADH2 through the ETC. Quantum tunneling of electrons and much larger protons may facilitate this separation. Neuronal death may be viewed as a local increase in entropy requiring constant energy input to avoid. The ATP requirement of the brain may partially be used for avoidance of local entropy increase. Mitochondrial therapeutics seeks to correct deficiencies in ETC and OXPHOS.
... DNA lesions can be caused by endogenous factors such as spontaneous decay of the DNA molecule [49] or as a result of several cellular metabolic processes, including ROS, natural byproducts of metabolism capable of reacting with the DNA molecule. The increase in ROS is strongly associated with neurodegenerative diseases and aging [50][51][52]. However, it is not yet clear whether imbalanced ROS is the cause or consequence of many of these diseases, including those associated with deficiencies in DNA repair. ...
Article
Human genetic syndromes deficient in nucleotide excision repair (NER), such as xeroderma pigmentosum and Cockayne syndrome, may present neurological abnormalities and premature aging symptoms. Unrepaired endogenously generated DNA damage that hampers transcription is a strong candidate that contributes to the development of these severe effects in neuronal tissue. Endogenous lesions include those generated due to byproducts of cellular metabolisms, such as reactive oxygen species. This review presents much of the evidence on the mechanisms related to neurodegenerative processes associated with DNA damage responses. The primary focus is on the effects of the transcription machinery, including the accumulation of DNA•RNA hybrids (R-loops) that, in turn, influence DNA damage and repair metabolism. Moreover, several neuronal tissues present higher expression of long genes, a genomic subset more affected by DNA lesions, which may explain part of the neurological abnormalities in these patients. Also, neuronal tissues have different DNA repair capabilities that might result in different neurological consequences, as observed in patients and NER deficient animal models. The better understanding of how the accumulation of transcription blocking lesions can lead to neurological abnormalities and premature aging-like phenotypes may assist us in finding potential biomarkers and therapeutic targets that might improve the lives of these patients, as well as other neurological disorders in the general population.
... Neuronal cell death is likewise characteristic of NDGDs, as seen in AD [379,380], PD [381,382], MS [383][384][385], and ALS [331,385,386]. Potential mechanistic commonalities include mitochondrial dysfunction (AD [387][388][389], PD [390,391], MS [392][393][394], ALS [395][396][397]), as well as microglial activation/inflammation (AD [398][399][400][401][402], PD [403][404][405], MS [406][407][408][409], ALS [410][411][412]) and oxidative stress (AD [413][414][415][416], PD [413][414][415]417], MS [418][419][420][421], ALS [332,422,423]). ...
Article
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Increasing evidence links air pollution (AP) exposure to effects on the central nervous system structure and function. Particulate matter AP, especially the ultrafine (nanoparticle) components, can carry numerous metal and trace element contaminants that can reach the brain in utero and after birth. Excess brain exposure to either essential or non-essential elements can result in brain dyshomeostasis, which has been implicated in both neurodevelopmental disorders (NDDs; autism spectrum disorder, schizophrenia, and attention deficit hyperactivity disorder) and neurodegenerative diseases (NDGDs; Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, and amyotrophic lateral sclerosis). This review summarizes the current understanding of the extent to which the inhalational or intranasal instillation of metals reproduces in vivo the shared features of NDDs and NDGDs, including enlarged lateral ventricles, alterations in myelination, glutamatergic dysfunction, neuronal cell death, inflammation, microglial activation, oxidative stress, mitochondrial dysfunction, altered social behaviors, cognitive dysfunction, and impulsivity. Although evidence is limited to date, neuronal cell death, oxidative stress, and mitochondrial dysfunction are reproduced by numerous metals. Understanding the specific contribution of metals/trace elements to this neurotoxicity can guide the development of more realistic animal exposure models of human AP exposure and consequently lead to a more meaningful approach to mechanistic studies, potential intervention strategies, and regulatory requirements.
... Prompted by these encouraging results, we decided to draw the antioxidant profile of compound 12, since it is well-known that oxidative stress is connected with insurgence and exacerbation of neurodegenerative diseases [3,18,31,32]. In particular, the AQP-mediated antioxidant properties of RC-33 (i.e., 1-[3-(1,1′-biphen)-4-yl]butylpiperidine, our in-house developed selective S1R agonist) and 12 were evaluated in HeLa cells, following the procedures reported in our most recent studies [22]. ...
Article
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Sigma-1 receptor (S1R) is a promising molecular target for the development of novel effective therapies against neurodegenerative diseases. To speed up the discovery of new S1R modulators, herein we report the development of a reliable in silico protocol suitable to predict the affinity of small molecules against S1R. The docking method has been validated by comparing the computational calculated Ki values of a test set of new aryl-aminoalkyl-ketone with experimental determined binding affinity. The druggability profile of the new compounds, with particular reference to the ability to cross the Blood Brain Barrier (BBB) was further predicted in silico. Moreover, the selectivity over Sigma-2 receptor (S2R) and N-methyl-D-aspartate (NMDA) receptor, another protein involved in neurodegeneration, was evaluated. 1-([1,1'-biphenyl]-4-yl)-4-(piperidin-1-yl)butan-1-one (12) performed as the best compound and was further investigated for acetylcholinesterase (AchE) inhibitor activity and determination of antioxidant activity mediated by aquaporins (AQPs). With a good affinity against both S1R and NMDA receptor, good selectivity over S2R and favourable BBB penetration potential together with its AChE inhibitory activity and its ability to exert antioxidant effects through modulation of AQPs, 12 represents a viable candidate for further development as a neuroprotective agent.
... Amyotrophic lateral sclerosis (ALS) is a fatal disorder characterized by a specific and progressive degeneration of upper and lower motor neurons followed by muscular atrophy [1][2][3][4][5][6][7][8][9]. ...
Article
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Amyotrophic lateral sclerosis (ALS) is a multifactorial and progressive neurodegenerative disease of unknown etiology. Due to ALS’s unpredictable onset and progression rate, the search for biomarkers that allow the detection and tracking of its development and therapeutic efficacy would be of significant medical value. Considering that alterations of energy supply are one of ALS’s main hallmarks and that a correlation has been established between gene expression in human brain tissue and peripheral blood mononuclear cells (PBMCs), the present work investigates whether changes in mitochondrial function could be used to monitor ALS. To achieve this goal, PBMCs from ALS patients and control subjects were used; blood sampling is a quite non-invasive method and is cost-effective. Different parameters were evaluated, namely cytosolic calcium levels, mitochondrial membrane potential, oxidative stress, and metabolic compounds levels, as well as mitochondrial dynamics and degradation. Altogether, we observed lower mitochondrial calcium uptake/retention, mitochondria depolarization, and redox homeostasis deregulation, in addition to a decrease in critical metabolic genes, a diminishment in mitochondrial biogenesis, and an augmentation in mitochondrial fission and autophagy-related gene expression. All of these changes can contribute to the decreased ATP and pyruvate levels observed in ALS PBMCs. Our data indicate that PBMCs from ALS patients show a significant mitochondrial dysfunction, resembling several findings from ALS’ neural cells/models, which could be exploited as a powerful tool in ALS research. Our findings can also guide future studies on new pharmacological interventions for ALS since assessments of brain samples are challenging and represent a relevant limited strategy. Graphical abstract
Article
Objective Proteomic elucidation is an essential step in improving our understanding of the biological properties of proteins in amyotrophic lateral sclerosis (ALS). Methods Preliminary proteomic analysis was performed on the spinal cord and brain of SOD1 G93A (TG) and wild-type (WT) mice using isobaric tags for relative and absolute quantitation. Results Partial up- and downregulated proteins showing significant differences between TG and WT mice were identified, of which 105 proteins overlapped with differentially expressed proteins in both the spinal cord and brain of progression mice. Bioinformatic analyses using Gene Ontology, a cluster of orthologous groups, and Kyoto Encyclopedia of Genes and Genomes pathway revealed that the significantly up- and downregulated proteins represented multiple biological functions closely related to ALS, with 105 overlapping differentially expressed proteins in the spinal cord and brain at the progression stage of TG mice closely related to 122 pathways. Differentially expressed proteins involved in a set of molecular functions play essential roles in maintaining neural cell survival. Conclusion This study provides additional proteomic profiles of TG mice, including potential overlapping proteins in both the spinal cord and brain that participate in pathogenesis, as well as novel insights into the up- and downregulation of proteins involved in the pathogenesis of ALS.
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Covering the spectrum of cognitive decline in aging using illustrative cases, from mild impairment to dementia, this set of case studies offers a wide-ranging guide for trainees and clinicians. This second volume includes updated research diagnostic criteria and details of new imaging technology, including novel biomarkers such as PET amyloid and tau, to inform readers in clinical practice. Each case includes a clinical history, examination findings and special investigations, followed by diagnosis and discussion, to encourage clinical reasoning, integrative thinking, and problem-solving skills. To reinforce diagnostic skills, the cases include careful analysis of individual presenting patterns and up-to-date information on diagnostic classification and tools. The reader will be able to distinguish patients who need reassurance, closer follow-up or immediate referral to specialized services. With an international authorship, this book is for trainees and clinicians in neurology, psychiatry and neuropsychology.
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FUS-proteinopathies, a group of heterogeneous disorders including ALS-FUS and FTLD-FUS, are characterized by the formation of inclusion bodies containing the nuclear protein FUS in the affected patients. However, the underlying molecular and cellular defects remain unclear. Here we provide evidence for mitochondrial localization of FUS and its induction of mitochondrial damage. Remarkably, FTLD-FUS brain samples show increased FUS expression and mitochondrial defects. Biochemical and genetic data demonstrate that FUS interacts with a mitochondrial chaperonin, HSP60, and that FUS translocation to mitochondria is, at least in part, mediated by HSP60. Down-regulating HSP60 reduces mitochondrially localized FUS and partially rescues mitochondrial defects and neurodegenerative phenotypes caused by FUS expression in transgenic flies. This is the first report of direct mitochondrial targeting by a nuclear protein associated with neurodegeneration, suggesting that mitochondrial impairment may represent a critical event in different forms of FUS-proteinopathies and a common pathological feature for both ALS-FUS and FTLD-FUS. Our study offers a potential explanation for the highly heterogeneous nature and complex genetic presentation of different forms of FUS-proteinopathies. Our data also suggest that mitochondrial damage may be a target in future development of diagnostic and therapeutic tools for FUS-proteinopathies, a group of devastating neurodegenerative diseases.
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Most of the mitochondrial proteome originates from nuclear genes and is transported into the mitochondria after synthesis in the cytosol. Complex machineries which maintain the specificity of protein import and sorting include the TIM23 translocase responsible for the transfer of precursor proteins into the matrix, and the mitochondrial intermembrane space import and assembly (MIA) machinery required for the biogenesis of intermembrane space proteins. Dysfunction of mitochondrial protein sorting pathways results in diminishing specific substrate proteins, followed by systemic pathology of the organelle and organismal death. The cellular responses caused by accumulation of mitochondrial precursor proteins in the cytosol are mainly unknown. Here we present a comprehensive picture of the changes in the cellular transcriptome and proteome in response to a mitochondrial import defect and precursor over-accumulation stress. Pathways were identified that protect the cell against mitochondrial biogenesis defects by inhibiting protein synthesis and by activation of the proteasome, a major machine for cellular protein clearance. Proteasomal activity is modulated in proportion to the quantity of mislocalized mitochondrial precursor proteins in the cytosol. We propose that this type of unfolded protein response activated by mistargeting of proteins (UPRam) is beneficial for the cells. UPRam provides a means for buffering the consequences of physiological slowdown in mitochondrial protein import and for counteracting pathologies that are caused or contributed by mitochondrial dysfunction.
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The hexanucleotide repeat expansion (HRE) GGGGCC (G4C2) in C9orf72 is the most common cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Recent studies support an HRE RNA gain-of-function mechanism of neurotoxicity, and we previously identified protein interactors for the G4C2 RNA including RanGAP1. A candidate-based genetic screen in Drosophila expressing 30 G4C2 repeats identified RanGAP (Drosophila orthologue of human RanGAP1), a key regulator of nucleocytoplasmic transport, as a potent suppressor of neurodegeneration. Enhancing nuclear import or suppressing nuclear export of proteins also suppresses neurodegeneration. RanGAP physically interacts with HRE RNA and is mislocalized in HRE-expressing flies, neurons from C9orf72 ALS patient-derived induced pluripotent stem cells (iPSC-derived neurons), and in C9orf72 ALS patient brain tissue. Nuclear import is impaired as a result of HRE expression in the fly model and in C9orf72 iPSC-derived neurons, and these deficits are rescued by small molecules and antisense oligonucleotides targeting the HRE G-quadruplexes. Nucleocytoplasmic transport defects may be a fundamental pathway for ALS and FTD that is amenable to pharmacotherapeutic intervention.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by loss of motor neuron-like cells. Mutations in the RNA- and DNA-binding proteins, fused in sarcoma (FUS) and transactive response DNA-binding protein 43kda (TDP-43) are responsible for 5-10% of familial and 1% of sporadic ALS cases. Importantly, aggregation of misfolded FUS or TDP-43 is also characteristic of several neurodegenerative disorders in addition to ALS, including frontotemporal lobar degeneration (FTLD). Moreover, splicing deregulation of FUS and TDP-43 target genes as well as mitochondrial abnormalities are both associated with disease-causing FUS and TDP-43 mutants. While progress has been made to understand the functions of these proteins, the exact mechanisms by which FUS and TDP-43 cause ALS remain unknown. Recently we discovered that, in addition to being up-regulated in spinal cords of ALS patients, the novel protein oxidative resistance 1 (Oxr1) protects neurons from oxidative stress-induced apoptosis. To further understand the function of Oxr1, we present here the first interaction study of the protein. We show that Oxr1 binds to Fus and Tdp-43 and that certain ALS-associated mutations in Fus and Tdp-43 affect their Oxr1 binding properties. We further demonstrate that increasing Oxr1 levels in cells expressing specific Fus and Tdp-43 mutants improves the three main cellular features associated with ALS: cytoplasmic mis-localisation and aggregation, splicing changes of a mitochondrial gene, and mitochondrial defects. Taken together, these findings suggest that OXR1 may have therapeutic benefits for the treatment of ALS and related neurodegenerative disorders with TDP-43 pathology.
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Mammalian cells remove misfolded proteins using various proteolytic systems, including the ubiquitin (Ub)-proteasome system (UPS), chaperone mediated autophagy (CMA) and macroautophagy. The majority of misfolded proteins are degraded by the UPS, in which Ub-conjugated substrates are deubiquitinated, unfolded and cleaved into small peptides when passing through the narrow chamber of the proteasome. The substrates that expose a specific degradation signal, the KFERQ sequence motif, can be delivered to and degraded in lysosomes via the CMA. Aggregation-prone substrates resistant to both the UPS and the CMA can be degraded by macroautophagy, in which cargoes are segregated into autophagosomes before degradation by lysosomal hydrolases. Although most misfolded and aggregated proteins in the human proteome can be degraded by cellular protein quality control, some native and mutant proteins prone to aggregation into β-sheet-enriched oligomers are resistant to all known proteolytic pathways and can thus grow into inclusion bodies or extracellular plaques. The accumulation of protease-resistant misfolded and aggregated proteins is a common mechanism underlying protein misfolding disorders, including neurodegenerative diseases such as Huntington’s disease (HD), Alzheimer’s disease (AD), Parkinson’s disease (PD), prion diseases and Amyotrophic Lateral Sclerosis (ALS). In this review, we provide an overview of the proteolytic pathways in neurons, with an emphasis on the UPS, CMA and macroautophagy, and discuss the role of protein quality control in the degradation of pathogenic proteins in neurodegenerative diseases. Additionally, we examine existing putative therapeutic strategies to efficiently remove cytotoxic proteins from degenerating neurons.
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Research on mitochondria in the last years has been characterized by the fundamental finding that the morphology of mitochondria is deeply connected to the regulation of a vast number of different processes, including oxidative phosphorylation and ATP production, calcium buffering, and apoptosis. This has immediately focused the attention of the neuroscience community to the possible involvement of mitochondrial dynamism, the process underlying morphological features of mitochondria, in neurodegeneration, where mitochondrial dysfunction is believed to represent an important contributing event, or even a primary causative factor. Amyotrophic Lateral Sclerosis (ALS), a disease of motor neurons and their neighboring cells, has long been considered as a neurodegenerative disease with an important mitochondrial issue. Yet, whether mitochondria have a causative, primary role in the pathogenic process has always been debated, and the specific defects which account for this role are elusive. Here we discuss recent genetic advances suggesting that defective mitochondrial dynamism is primarily involved in the pathogenic mechanisms of ALS, and that foster the longstanding concept that disruption of mitochondrial function is a vulnerable factor for motor neurons.
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Protein homeostasis is critical for cell survival and functions during stress and is regulated at both RNA and protein levels. However, how the cell integrates RNA-processing programs with post-translational protein quality control systems is unknown. Transactive response DNA-binding protein (TARDBP/TDP-43) is an RNA-processing protein that is involved in the pathogenesis of major neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Here, we report a conserved role for TDP-43, from C. elegans to mammals, in the regulation of protein clearance via activation of FOXO transcription factors. In response to proteotoxic insults, TDP-43 redistributes from the nucleus to the cytoplasm, promoting nuclear translocation of FOXOs and relieving an inhibition of FOXO activity in the nucleus. The interaction between TDP-43 and the FOXO pathway in mammalian cells is mediated by their competitive binding to 14-3-3 proteins. Consistent with FOXO-dependent protein quality control, TDP-43 regulates the levels of misfolded proteins. Therefore, TDP-43 mediates stress responses and couples the regulation of RNA metabolism and protein quality control in a FOXO-dependent manner. The results suggest that compromising the function of TDP-43 in regulating protein homeostasis may contribute to the pathogenesis of related neurodegenerative diseases.
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Fused in sarcoma/translocated in liposarcoma (FUS/TLS or FUS) is a multifunctional DNA-/RNA-binding protein that is involved in a variety of cellular functions including transcription, protein translation, RNA splicing, and transport. FUS was initially identified as a fusion oncoprotein, and thus, the early literature focused on the role of FUS in cancer. With the recent discoveries revealing the role of FUS in neurodegenerative diseases, namely amyotrophic lateral sclerosis and frontotemporal lobar degeneration, there has been a renewed interest in elucidating the normal functions of FUS. It is not clear which, if any, endogenous functions of FUS are involved in disease pathogenesis. Here, we review what is currently known regarding the normal functions of FUS with an emphasis on DNA damage repair, RNA processing, and cellular stress response. Further, we discuss how ALS-causing mutations can potentially alter the role of FUS in these pathways, thereby contributing to disease pathogenesis.
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TDP-43 aggregates are the neurohistological landmark of diseases like Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Dementia (FTD). Their role in the pathogenesis of these conditions is not yet clear mainly due to the lack of proper models of aggregation that may allow the study of the mechanism of formation, their interactions with other cellular components, and their effect on the cell metabolism. In this work, we have used tandem repeats of the prion like Q/N-rich region of TDP-43 fused to additional TDP-43 protein sequences to trigger aggregate formation in neuronal and non-neuronal cell lines. At the functional level, these aggregates are able to sequester endogenous TDP-43 depleting its nuclear levels and inducing loss of function at the pre-mRNA splicing level. No apparent direct cellular toxicity of the aggregates seems to be present beyond the lack of functional TDP-43. To our knowledge, this is the only system that achieves full functional TDP 43 depletion with effects similar to RNAi depletion or gene deletion. As a result, this model will prove useful to investigate the loss-of-function effects mediated by TDP-43 aggregation within cells without affecting the expression of the endogenous gene. We have identified the N terminus sequence of TDP-43 as the domain that enhances its interaction with the aggregates and its insolubilization. These data show for the first time that cellular TDP-43 aggregation can lead to total loss of function and to defective splicing of TDP-43 dependent splicing events in endogenous genes.
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The identification of genetic and epigenetic factors that are associated with an increased risk of developing amyotrophic lateral sclerosis (ALS), or that modify the age of onset or rate of progression, requires a multimodal research strategy, facilitated through international collaboration. The discovery of several ALS genes strongly linked to RNA biology, the proteasome pathway, and axonal transport suggest they have an important role in pathogenesis, but the immense complexity of these processes is also apparent. The increasing rate of genetic discoveries brings the hope of designing more targeted and efficacious therapies.
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The neurodegenerative diseases are a diverse group of disorders characterized by progressive loss of specific groups of neurons. These diseases affect different populations, and have a variable age of onset, clinical symptoms, and pathological findings. Variants in the FUS gene, which encodes an RNA-binding protein, have been identified as causative or risk factors for amyotrophic lateral sclerosis (ALS), essential tremor and rare forms of frontotemporal lobar degeneration (FTLD). Additionally, abnormal aggregation of FUS protein has been reported in multiple neurodegenerative diseases, including ALS, FTLD and the polyglutamine diseases, suggesting a role for FUS in the pathogenesis of these neurodegenerative diseases. This Review summarizes current understanding of the normal function of FUS, and describes its role in the pathology of ALS, FTLD, essential tremor and other neurodegenerative diseases. Comments on the underlying pathogenetic mechanisms of these FUS-related disorders are included. Finally, the clinical implications of recent advances in FUS research are discussed. Further understanding of the role of FUS in neurodegenerative diseases might lead to improvements in the treatment and prevention of these disorders.
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A hexanucleotide repeat expansion within a non-coding region of the C9ORF72 gene is the most common mutation causative of frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Elucidating how this bidirectionally transcribed G4C2·C4G2 expanded repeat causes "C9FTLD/ALS" has since become an important goal of the field. Likely pathogenic mechanisms include toxicity induced by repeat-containing RNAs, and loss of C9orf72 function due to epigenetic changes resulting in decreased C9ORF72 mRNA expression. With regards to the former, sense and antisense transcripts of the expanded repeat aberrantly interact with various RNA-binding proteins and form discrete nuclear structures, termed RNA foci. These foci have the capacity to sequester select RNA-binding proteins, thereby impairing their function. (G4C2)exp and (C4G2)exp transcripts also succumb to an alternative fate: repeat-associated non-ATG (RAN) translation. This unconventional mode of translation, which occurs in the absence of an initiating codon, results in the abnormal production of poly(GA), poly(GP), poly(GR), poly(PR) and poly(PA) peptides, collectively referred to as C9RAN proteins. C9RAN proteins form neuronal inclusions throughout the central nervous system of C9FTLD/ALS patients and may contribute to disease pathogenesis. This review aims to summarize the important findings from studies examining mechanisms of disease in C9FTLD/ALS, and will also highlight some of the many questions in need of further investigation.
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The ability to respond to various intracellular and/or extracellular stresses allows the organism to adapt to changing environmental conditions and drives evolution. It is now well accepted that a progressive decline of the efficiency of stress response pathways occurs with aging. In this context, a correct proteostasis is essential for the functionality of the cell, and its dysfunction has been associated with protein aggregation and age-related degenerative diseases. Complex response mechanisms have evolved to deal with unfolded protein stress in different subcellular compartments and their moderate activation translates into positive effects on health. In this review, we focus on the mitochondrial unfolded protein response (UPR(mt)), a response to proteotoxic stress specifically in mitochondria, an organelle with a wide array of fundamental functions, most notably the harvesting of energy from food and the control of cell death. We compare UPR(mt) with the extensively characterized cytosolic heat shock response (HSR) and the unfolded protein response in endoplasmic reticulum (UPR(ER)), and discuss the current knowledge about UPR(mt) signaling pathways as well as their potential involvement in physiology.
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TDP-43 and FUS are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), and loss of function of either protein contributes to these neurodegenerative conditions. To elucidate the TDP-43- and FUS-regulated pathophysiological RNA metabolism cascades, we assessed the differential gene expression and alternative splicing profiles related to regulation by either TDP-43 or FUS in primary cortical neurons. These profiles overlapped by >25% with respect to gene expression and >9% with respect to alternative splicing. The shared downstream RNA targets of TDP-43 and FUS may form a common pathway in the neurodegenerative processes of ALS/FTLD.
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TDP-43 aggregation in the cytoplasm or nucleus is a key feature of the pathology of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), and is observed in numerous other neurodegenerative diseases, including Alzheimer's disease. Despite this fact, the inciting events leading to TDP-43 aggregation remain unclear. We observed that endogenous TDP-43 undergoes reversible aggregation in the nucleus after the heat shock, and that this behavior is mediated by the C-terminal prion domain. Substitution of the prion domain from TIA-1 or an authentic yeast prion domain from RNQ1 into TDP-43 can completely recapitulate heat shock induced aggregation. TDP-43 is constitutively bound to members of the Hsp40/Hsp70 family, and we found that heat shock induced TDP-43 aggregation is mediated by availability of these chaperones interacting with the inherently disordered C-terminal prion domain. Finally we observed that aggregation of TDP-43 during heat shock led to decreased binding to hnRNPA1, and a change in TDP-43 RNA binding partners suggesting that TDP-43 aggregation alters its function in response to misfolded protein stress. These findings indicate that TDP-43 shares properties with physiologic prions from yeast, in that self-aggregation is mediated by a Q/N rich disordered domain, is modulated by chaperone proteins, and leads to altered function of the protein. Furthermore they indicate that TDP-43 aggregation is regulated by chaperone availability, explaining the recurrent observation of TDP-43 aggregates in degenerative diseases of both brain and muscle where protein homeostasis is disrupted.
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the devastating disease.
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Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1125-6) contains supplementary material, which is available to authorized users.
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