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Oxidative stress and mitochondrial damage in the pathogenesis of ALS: New perspectives
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.
... 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]. ...
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). ...
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). ...
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]. ...
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.
... As Ingre et al. (2015) noted, different risk factors have been studied independently of each other, but little work has been done to study how they may interact and what factors may predispose a person to those circumstances. Further, the onset location of ALS may be, in part, due to the differences in the vulnerability of nerves to exposure to proximal risk factors linked to ALS development (Brown, Lockwood, and Sonawane, 2005;Aschbacher et al., 2013;D'Amico et al., 2013;Bozzo et al., 2017). ...
... Higher levels of chronic stress for women leads to higher levels of oxidative stress via the repeated activation of the HPA axis, causing damage to the cells in the body, including the nervous system (Aschbacher et al., 2013). Oxidative stress has been implicated as one potential trigger for ALS, and may influence the onset location (Bozzo et al., 2017). Gender, however, does not seem to affect survival rates between women and men, meaning the oxidative stress may only trigger ALS, but not influence mortality (McCombe and Henderson, 2010). ...
... cortisol) and damage to the nervous system (e.g. oxidative stress) (Fidler et al, 2011;Bozzo et al., 2017). The addition of a module to the registry asking about life events and chronic stressors, in combination with biomarker data, could begin to clarify the connection between stress and ALS. ...
This dissertation focuses on the implications of social position and life course on the experience of Amyotrophic Lateral Sclerosis (ALS). Using a sociology in medicine frame, I test three theoretical perspectives (fundamental cause theory, social determinants of health, and life course theory) to determine the influence of social conditions on the development and progression of, and medical care for, people with ALS (pALS). Further, I use ALS as an exemplar of the need for a sociology of disease. Using the Amyotrophic Lateral Sclerosis National Registry, I first assess the association of social position with the reported onset location at the time of diagnosis of ALS. Second, I assess the influence of social position on the time between reported date of symptom development and diagnosis. The final study evaluates the odds of reporting several types of medical care dependent on the position in the life course. Results indicate that social position (race/ethnicity, gender, and education) influence the experience of the onset of ALS. Further, position in the life course is associated with the reporting of onset location, with those at older ages being more likely to report bulbar or global onset in contrast to limb onset. Position in the life course is also associated with symptoms of ALS, with older persons with ALS (pALS) experiencing symptoms earlier, often prior to diagnosis. Social position and position in the life course also influenced the adoption of life-extending medical care for pALS, with younger pALS adopting more of these interventions. Overall, the results indicate that even in a rare disease with an unknown cause, fundamental cause theory, the social determinants of health, and life course theory provide a valuable framework for understanding the experience of ALS. These theories, however, need refinement when used in the sociology of disease. Additionally, the results are evidence of a need for a sociology of disease. Finally, the results highlight the need for more inclusive research designs, as well as additional qualitative and quantitative work in understanding how social position shapes the lived experience of ALS. Advisor: Julia McQuillan
... 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]. ...
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]. ...
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. ...
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 SOD1 G93A 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 Ca ²⁺ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca ²⁺ 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.
... 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]. ...
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]. ...
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. ...
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]. ...
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. ...
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]. ...
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. ...
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.
... 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]. ...
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]. ...
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]. ...
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. ...
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]. ...
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. ...
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]. ...
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] ...
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. ...
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]). ...
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]. ...
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]. ...
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
... Like rofecoxib, several other anti-neuroinflammatory interventions have also yielded better effects in delaying disease onset than in prolonging survival in SOD1 G93A mice, such as cromolyn sodium (Granucci et al., 2019), tempol (Chiarotto et al., 2019), and lysine acetylsalicylate (Barneoud and Curet, 1999). Third, many other mechanisms besides neuroinflammation have been confirmed to be related to the pathogenesis of ALS, such as protein aggregation (Brown and Al-Chalabi, 2017), oxidative stress (Bozzo et al., 2017), glutamate excitotoxicity (Blasco et al., 2014), autophagy abnormality (Nassif and Hetz, 2011), mitochondrial structure and function abnormality (Golpich et al., 2016), and endoplasmic reticulum stress (Matus et al., 2013). Therefore, modestly prolonging the survival of SOD1 G93A mice by rofecoxib is accepted by only inhibiting neuroinflammation. ...
Cyclooxygenase-2 (COX-2) is reported to be activated during the course of amyotrophic lateral sclerosis (ALS) development and progression. However, the roles of COX-2 in aggravating ALS and the underlying mechanism have been largely overlooked. To reveal the mechanisms, the canonical SOD1G93A mouse model was used as an experimental model for ALS in the current study. In addition, a specific inhibitor of COX-2 activity, rofecoxib, was orally administered to SOD1G93A mice. With this in vivo approach, we revealed that COX-2 proinflammatory signaling cascades were inhibited by rofecoxib in SOD1G93A mice. Specifically, the protein levels of COX-2, interleukin (IL)-1β, and tumor necrosis factor (TNF)-α were elevated as a result of activation of astrocytes and microglia during the course of ALS development and progression. These proinflammatory reactions may contribute to the death of neurons by triggering the movement of astrocytes and microglia to neurons in the context of ALS. Treatment with rofecoxib alleviated this close association between glial cells and neurons and significantly decreased the density of inflammatory cells, which helped to restore the number of motor neurons in SOD1G93A mice. Mechanistically, rofecoxib treatment decreased the expression of COX-2 and its downstream signaling targets, including IL-1β and TNF-α, by deactivating glial cells, which in turn ameliorated the progression of SOD1G93A mice by postponing disease onset and modestly prolonging survival. Collectively, these results provide novel insights into the mechanisms of ALS and aid in the development of new drugs to improve the clinical treatment of ALS.
... ALS is a neuromuscular disease among various neurodegenerative diseases, which usually occurs after the age of 50 and fatal respiratory paralysis occurs within 3-5 years after diagnosis, which is life-threatening [87,88]. In the process of ALS formation, RNA oxidation may change the structure of proteins, resulting in abnormal protein inclusion bodies gathering in the cytoplasm, and aggregates can, in turn, induce the production of ROS in cytoplasm and mitochondria, resulting in a harmful cycle in this way, thus promoting the formation of ALS [89,90]. ...
In the history of nucleic acid research, DNA has always been the main research focus. After the sketch of the human genome was completed in 2000, RNA has been started to gain more attention due to its abundancies in the cell and its essential role in cellular physiology and pathologies. Recent studies have shown that RNAs are susceptible to oxidative damage and oxidized RNA is able to break the RNA strand, and affect the protein synthesis, which can lead to cell degradation and cell death. Studies have shown that RNA oxidation is one of the early events in the formation and development of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. However, its molecular mechanism, as well as its impact on these diseases, are still unclear. In this article, we review the different types of RNA oxidative damage and the neurodegenerative diseases that are reported to be associated with RNA oxidative damage. In addition, we discuss recent findings on the association between RNA oxidative damage and the development of neurodegenerative diseases, which will have great significance for the development of novel strategies for the prevention and treatment of these diseases.
... Some of the highly penetrant genes include Cu/Zn superoxide dismutase 1 (SOD1), Fused in Sarcoma (FUS) (4% fALS and < 1% sALS), C9orf72, CHCHD10, TAR DNAbinding protein 43 (TDP-43) (5% fALS and < 1% sALS), and Sqstm1/p62 (Seetharaman et al., 2009;Blair et al., 2010;Chio et al., 2011;Ludolph et al., 2012;Majounie et al., 2012;Gijselinck et al., 2015;Webster et al., 2016;Carri et al., 2017;Collins and Bowser, 2017;Frick et al., 2018). Indeed, these genetic mutations correspond to ∼68% of fALS cases, while 11% appear to be related to increased susceptibility to sALS (Bozzo et al., 2017;Webster et al., 2018). Mutations in the acetylcholine nicotinic receptors (Sabatelli et al., 2009) and in the charged multivesicular body protein 2b (CHMP2B) (Cox et al., 2010), previously known as chromatin-modifying protein 2b, are also frequent in sALS. ...
Amyotrophic lateral sclerosis (ALS) is a progressive and devastating multifactorial neurodegenerative disorder. Although the pathogenesis of ALS is still not completely understood, numerous studies suggest that mitochondrial deregulation may be implicated in its onset and progression. Interestingly, mitochondrial deregulation has also been associated with changes in neural stem cells (NSC) proliferation, differentiation, and migration. In this review, we highlight the importance of mitochondrial function for neurogenesis, and how both processes are correlated and may contribute to the pathogenesis of ALS; we have focused primarily on preclinical data from animal models of ALS, since to date no studies have evaluated this link using human samples. As there is currently no cure and no effective therapy to counteract ALS, we have also discussed how improving neurogenic function by epigenetic modulation could benefit ALS. In support of this hypothesis, changes in histone deacetylation can alter mitochondrial function, which in turn might ameliorate cellular proliferation as well as neuronal differentiation and migration. We propose that modulation of epigenetics, mitochondrial function, and neurogenesis might provide new hope for ALS patients, and studies exploring these new territories are warranted in the near future.
... However, elevated levels of oxidative markers (e.g. protein carbonyl levels), lipid peroxidation and oxidation of DNA/RNA, have been documented in patients with ALS (Barber & Shaw, 2010;Bogdanov et al., 2000;Chang et al., 2008;Cova et al., 2010;Robberecht, 2000;Shaw, Forrest, Ince, Richardson, & Wastell, 1995;Simpson, Henry, Henkel, Smith, & Appel, 2004). Similarly, increased oxidative stress is also prevalent in transgenic rodent models and iPSC lines of both sporadic and familial ALS cases (Bozzo, Mirra, & Carri, 2017;Lopez-Gonzalez et al., 2016). ...
Neuropeptide Y (NPY) is an endogenous peptide of the central and enteric nervous systems which has gained significant interest as a potential neuroprotective agent for treatment of neurodegenerative disease. Amyotrophic lateral sclerosis (ALS) is an aggressive and fatal neurodegenerative disease characterised by motor deficits and motor neuron loss. In ALS, recent evidence from ALS patients and animal models has indicated that NPY may have a role in the disease pathogenesis. Increased NPY levels were found to correlate with disease progression in ALS patients. Similarly, NPY expression is increased in the motor cortex of ALS mice by end‐stages of disease. Although the functional consequence of increased NPY levels in ALS is currently unknown, NPY has been shown to exert a diverse range of neuroprotective roles in other neurodegenerative diseases; through modulation of potassium channel activity, increased production of neurotrophins, inhibition of endoplasmic reticulum stress and autophagy, reduction of excitotoxicity, oxidative stress, neuroinflammation and hyperexcitability. Several of these mechanisms and signaling pathways are heavily implicated in the pathogenesis of ALS. Therefore, in this review, we discuss possible effects of NPY and NPY‐receptor signaling in the ALS disease context, as determining NPYs contribution to, or impact on, ALS disease mechanisms will be essential for future studies investigating the NPY system as a therapeutic strategy in this devastating disease.
... Besides being recognized as a non-cell autonomous disease, the significant role of neuroinflammation in the disease progression [116], and early changes in astrocytic gene expression [117] suggest that neuroinflammation may precede motoneuronal loss pre-symptomatically. Moreover, oxidative stress and mitochondrial dysfunction are well-described factors in the pathogenesis of ALS [118], both of which are known to induce inflammasome activation [119]. ...
Aging is characterized by a chronic low-grade sterile inflammation dubbed as inflammaging, which in part originates from accumulating cellular debris. These, acting as danger signals with many intrinsic factors such as cytokines, are sensed by a network of pattern recognition receptors and other cognate receptors, leading to the activation of inflammasomes. Due to the inflammasome activity-dependent increase in the levels of pro-inflammatory interleukins (IL-1β, IL-18), inflammation is initiated, resulting in tissue injury in various organs, the brain and the spinal cord included. Similarly, in age-related diseases of the central nervous system (CNS), inflammasome activation is a prominent moment, in which cells of the neurovascular unit occupy a significant position. In this review, we discuss the inflammatory changes in normal aging and summarize the current knowledge on the role of inflammasomes and contributing mechanisms in common CNS diseases, namely Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and stroke, all of which occur more frequently with aging.
... The oxidative stress has been widely acknowledged by most ALS investigators [60,61] and edaravone, a freeradical scavenger, was approved for use for clinically treating ALS patients by the American Food and Drug Administration [62,63]. Although oxidative stress is not the sole pathogenetic factor and edaravone could not yet stop the progression of ALS, the importance of oxidative stress in the pathogenesis of ALS is noticeable, and it is necessary to explore new free radical scavengers for the ALS treatment. ...
All-trans retinoic acid (ATRA), a ligand of retinoic acid receptors, could regulate various biological processes by activating retinoic acid signals. Recent studies suggested that ATRA displays multiple neuroprotective effects and thereby alleviates the disease progression in a variety of neurological diseases. Our previous studies found that the impaired retinoic acid signal decreased ALDH1A2, an essential synthetase of ATRA, in the spinal cord of ALS mice. Here, we evaluated the neuroprotective and neurorestorative effects of ATRA in a SOD1-G93A transgenic mice model of ALS. We administrated ATRA(3 mg/kg) daily from the onset stage to the progression stage for 5 weeks. Behavioral tests showed that ATRA improved the forelimb grip strength in ALS mice and may slow the disease progression, but not the body weight. ATRA could completely reverse the impaired retinoic acid receptor alpha (RARα) signal in the spinal cord of ALS mice. This effect was accompanied by enhancing the degradation of misfolded proteins via the ubiquitin-proteasome system, regulating the oxidative stress, inhibiting the astrocyte activation, and promoting the neurotrophic signal recovery. Our findings are the first to indicate that the damaged retinoic acid signal is involved in the pathogenesis of ALS, and ATRA could induce the functional neuroprotection via repairing the damaged retinoic acid signal.
... The principal aggregates present in patients suffering ALS are ubiquitinated aggregates and can be either Lewy body-like hyaline inclusions or skein-like inclusions [75]. Ubiquitinated aggregates observed in ALS can induce ROS generation both in the cytosol and in mitochondria [76][77][78]. ...
Neurodegenerative diseases include a variety of pathologies such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, and so forth, which share many common characteristics such as oxidative stress, glycation, abnormal protein deposition, inflammation, and progressive neuronal loss. The last century has witnessed significant research to identify mechanisms and risk factors contributing to the complex etiopathogenesis of neurodegenerative diseases, such as genetic, vascular/metabolic, and lifestyle-related factors, which often co-occur and interact with each other. Apart from several environmental or genetic factors, in recent years, much evidence hints that impairment in redox homeostasis is a common mechanism in different neurological diseases. However, from a pharmacological perspective, oxidative stress is a difficult target, and antioxidants, the only strategy used so far, have been ineffective or even provoked side effects. In this review, we report an analysis of the recent literature on the role of oxidative stress in Alzheimer’s and Parkinson’s diseases as well as in amyotrophic lateral sclerosis, retinal ganglion cells, and ataxia. Moreover, the contribution of stem cells has been widely explored, looking at their potential in neuronal differentiation and reporting findings on their application in fighting oxidative stress in different neurodegenerative diseases. In particular, the exposure to mesenchymal stem cells or their secretome can be considered as a promising therapeutic strategy to enhance antioxidant capacity and neurotrophin expression while inhibiting pro-inflammatory cytokine secretion, which are common aspects of neurodegenerative pathologies. Further studies are needed to identify a tailored approach for each neurodegenerative disease in order to design more effective stem cell therapeutic strategies to prevent a broad range of neurodegenerative disorders.
... The exact composition of these extracts varies by manufacturer. Ginkgo extracts has been reported in vitro to be able to neutralize oxidative stress (26)(27)(28), which is theoretically of benefit in ALS (29). In a single study with a mutant mouse model of ALS, a standardized extract of ginkgo (Egb 761), was shown to improve survival and slow lumbar-region motor neuron death (30). ...
... Markers for OS have been determined in the cerebrospinal fluid (CSF), tissues, blood and urine of patients with ALS (Blasco et al., 2017). After postmortem analysis of neuronal tissues in sALS and fALS patients, an increase of OS biomarkers was noted in proteins, lipids and DNA (Beal, 2002;Agar and Durham, 2003;Kim et al., 2003;Turner et al., 2013;Bozzo et al., 2016). The most frequently studied biomarkers include: carbonylated and/or glycosylated proteins, lipid peroxidation and DNA damage (Shibata et al., 2002). ...
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that produces a selective loss of the motor neurons of the spinal cord, brain stem and motor cortex. Oxidative stress (OS) associated with mitochondrial dysfunction and the deterioration of the electron transport chain has been shown to be a factor that contributes to neurodegeneration and plays a potential role in the pathogenesis of ALS. The regions of the central nervous system affected have high levels of reactive oxygen species (ROS) and reduced antioxidant defenses. Scientific studies propose treatment with antioxidants to combat the characteristic OS and the regeneration of nicotinamide adenine dinucleotide (NAD+) levels by the use of precursors. This review examines the possible roles of nicotinamide riboside and pterostilbene as therapeutic strategies in ALS.
... ALS, also known as Lou Gehrig's disease is rare but progressive and fatal motor neuron disease mainly affecting the neurons in the brain and spinal cord associated with voluntary muscular movements. Although patients portray variability in site, duration and age of disease onset, degree of cognitive deficits, etc. death invariably occurs in majority of the cases due to respiratory failure usually within 2-5 years post-diagnosis (Bozzo et al., 2017). It is mostly diagnosed on average in people falling in the age group of 55 to 65 years of age with around 2 in 100,000 people are diagnosed with ALS. ...
Reactive oxygen species are generated as a by-product of routine biochemical reactions. However, dysfunction of the antioxidant system or mutations in gene function may result in the elevated production of the pro-oxidant species. Modified endogenous molecules due to chemical interactions with increased levels of reactive oxygen and nitrogen species in the cellular microenvironment can be termed as biomarkers of oxidative stress. 3-Nitrotyrosine is one such promising biomarker of oxidative stress formed due to nitration of protein-bound and free tyrosine residues by reactive peroxynitrite molecules. Nitration of proteins at the sub-cellular level results in conformational alterations that damage the cytoskeleton and result in neurodegeneration. In this review, we summarized the role of oxidative/nitrosative processes as a contributing factor for progressive neurodegeneration in Alzheimer’s Disease, Parkinson’s Disease, Huntington’s Disease, Lou Gehrig’s disease and Prion Disease. The selective tyrosine protein nitration of major marker proteins in related pathologies have been discussed. The alteration in 3-Nitrotyrosine profile occurs well before any symptoms appear and can be considered as a potential target for early diagnosis of neurodegenerative diseases. Furthermore, the reduction in 3-Nitrotyrosine levels in response to treatment with neuroprotective has been highlighted which is indicative of the importance of this particular marker in oxidative stress-related brain and central nervous system pathologies.
... Notably, snRNP assembly function of the SMN complex was found to be inhibited by oxidative stress in a dose-dependent manner 110 . This observation adds to the plethora of evidence showing that oxidative stress perturbs RNA metabolism (reviewed in ref. 111 ). Thus, it is reasonable to speculate that oxidative stress is a modifying factor for Gemin3 function in snRNP synthesis as part of the SMN complex. ...
The predominant motor neuron disease in infants and adults is spinal muscular atrophy (SMA) and amyotrophic lateral sclerosis (ALS), respectively. SMA is caused by insufficient levels of the Survival Motor Neuron (SMN) protein, which operates as part of the multiprotein SMN complex that includes the DEAD-box RNA helicase Gemin3/DDX20/DP103. C9orf72, SOD1, TDP-43 and FUS are ranked as the four major genes causing familial ALS. Accumulating evidence has revealed a surprising molecular overlap between SMA and ALS. Here, we ask the question of whether Drosophila can also be exploited to study shared pathogenic pathways. Focusing on motor behaviour, muscle mass and survival, we show that disruption of either TBPH/TDP-43 or Caz/FUS enhance defects associated with Gemin3 loss-of-function. Gemin3-associated neuromuscular junction overgrowth was however suppressed. Sod1 depletion had a modifying effect in late adulthood. We also show that Gemin3 self-interacts and Gem3ΔN, a helicase domain deletion mutant, retains the ability to interact with its wild-type counterpart. Importantly, mutant:wild-type dimers are favoured more than wild-type:wild-type dimers. In addition to reinforcing the link between SMA and ALS, further exploration of mechanistic overlaps is now possible in a genetically tractable model organism. Notably, Gemin3 can be elevated to a candidate for modifying motor neuron degeneration.
... The Amyotrophic Lateral Sclerosis (ALS) is a progressive and fatal neurodegenerative disorder (1)(2)(3). ALS, also known as Lou Gehrig's disease, has an incidence of 2.5 cases per 100,000 people/year and a prevalence of 4-6:100,000; definitely, it is the most common motor neuron disorder (4). Therefore, ALS has not being considered a rare disease once its developing risk is 1/400-1/700 (5). ...
Background: The development of strategies that could not only efficiently detect the onset of Amyotrophic Lateral Sclerosis (ALS), a fatal neurodegenerative disorder with no cure but also predict its development and evaluate therapeutic intervention would be of great value. In this respect, the metabolic status of ALS patients has called attention. Hence, this study aimed to investigate the potential correlation between changes in ALS's metabolic parameters with the disease outcome in a systematic review. Methods: The manuscripts were manually searched within different databases (PubMed, Web of Science and Cochrane). The inclusion criteria were original articles and reviews about individuals with ALS and its survival, disease prognosis and metabolism (weight, cholesterol, hypertension, BMI, and glycaemia). The authors also established three different exclusion criteria: studies including ALS and other degenerative disorders, works including animal models and published before the year 2000. Results: In total, 29 papers were selected. From all manuscripts, only 82.8% ensured the participation of sALS patients. Also, 27.6% of selected studies described the presence of a genetic mutation. Regarding ALS prognosis, patient's age, the age of ALS onset, ALS duration and survival, <50% of the papers addressed these issues. Specifically, regarding metabolism, 65.5% of articles mentioned BMI, 20.7% mentioned any data concerning hypertension, 6.89% cardiovascular risk, 10.3% obesity, 13.78% diabetes and 10.3% glycaemia. Concerning lipid metabolism, more results were gathered, but still, they did not suffice to establish a correlation with ALS development. Conclusions: Altogether, the authors concluded that available information is not enough to establish a link between ALS and metabolism. In reality, less than half of the manuscripts evaluated show an association between both factors. Nonetheless, it is worth mentioning that metabolism does influence ALS, but not in a unique manner. There is a debate about patients' hypo- and hypermetabolism. Thus, to provide a reliable record, a public policy in which all research and clinical centers might assess the parameters discussed herein is suggested. Accordingly, this systematic review attempts to provide a comprehensible database to facilitate multicentered collaboration, validation, and clinical translation.
Amyotrophic lateral sclerosis (ALS) is a rare fatal motor neuron disease. Although many potential mechanisms have been proposed, the pathophysiology of the disease remains unknown. Currently available treatments can only delay the progression of the disease and prolong life expectancy by a few months. There is still no definitive cure for ALS, and the development of new treatments is limited by a lack of understanding of the underlying biological processes that trigger and promote neurodegeneration. Several scientific results suggest a neurovascular impairment in ALS providing perspectives for the development of new biomarkers and treatments. In this article, we performed a systematic review using PRISMA guidelines including PubMed, EmBase, GoogleScholar, and Web of Science Core Collection to analyze the scientific literature published between 2000 and 2021 discussing the neurocardiovascular involvement and ophthalmologic abnormalities in ALS. In total, 122 articles were included to establish this systematic review. Indeed, microvascular pathology seems to be involved in ALS, affecting all the neurovascular unit components. Retinal changes have also been recently highlighted without significant alteration of the visual pathways. Despite the peripheral location of the retina, it is considered as an extension of the central nervous system (CNS) as it displays similarities to the brain, the inner blood-retinal barrier, and the blood-brain barrier. This suggests that the eye could be considered as a 'window' into the brain in many CNS disorders. Thus, studying ocular manifestations of brain pathologies seems very promising in understanding neurodegenerative disorders, mainly ALS. Optical coherence tomography angiography (OCT-A) could therefore be a powerful approach for exploration of retinal microvascularization allowing to obtain new diagnostic and prognostic biomarkers of ALS.
Leveraging the phononic sensitivity and scalability of nano‐biointerfaces has accelerated the growth of unique and versatile biosensors. Graphene has the properties of a near‐ideal signal transducer, due to the strong coupling between its interfacial and phononic properties. This enables sensitive yet quick detection of surface interactions on graphene via Raman spectral analysis. The Raman‐active vibrational bands of graphene are demonstrated to be sensitive to structural, electrical, and interfacial modifications. This sensitivity is attributed to graphene's electron–phonon coupling and high quantum capacitance. The fundamental understanding of graphene phonons is crucial for developing reliable platforms for disease and infectious agent detection. This review provides a mechanistic explanation of these phenomena at the interface between graphene and various biosystems (including cancerous, bacterial, viral, and biophysical specimens) to set the foundation for next‐generation chemeo‐phononic medical devices. The interface of ultrasensitive graphene with various biological specimens enables the Raman‐active transducer to monitor the surface potential in real time. The underlying fundamentals of the phononic graphene transducer are explained, and the impact of the relevant works is described. Graphene's strong interfacial doping characteristic coupled with its phononics produces a robust chemeo‐phononic transducer that presents numerous novel biomedical applications.
The pathogenesis of amyotrophic lateral sclerosis (ALS) remains unclear. The recent studies have suggested that the protein abnormalities could play some important roles in ALS because several protein mutations were found in individuals with this disease. However, proteins that are currently known to be associated with ALS only explain the pathogenesis of this disease in a minority of cases, thus, further screening is needed to identify other ALS-related proteins. In this study, we systematically analyzed and compared the brain proteomic alterations between a mouse model of ALS, the Tg(SOD1*G93A)1Gur model, and wild-type mice using isobaric tags for relative and absolute quantitation (iTRAQ) as well as bioinformatics methods. The results revealed some significant up- and downregulated proteins at the different developmental stages in the ALS-like mice as well as the possibly related cellular components, molecular functions, biological processes, and pathways in the development of ALS. Our results identified some possible proteins that participate in the pathogenesis of ALS as well as the cellular components that are damaged by these proteins, we additionally identified the molecular functions, the biological processes, and the pathways of these proteins as well as the molecules that are associated with these pathways. This study represents an important preliminary investigation of the role of proteomic abnormalities in the pathogenesis of ALS, both in human patients and other animal models. We present some novel findings that may serve as a basis for further investigation of abnormal proteins that are involved in the pathogenesis of ALS.
Ficus hirta Vahl. has been reported to have hepatoprotective, antitumor, antibacterial functions, and is used to treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Ammonia nitrogen is one of the most common environmental stress factors in aquaculture. Long-term exposure to high concentrations of ammonia nitrogen can induce oxidative stress and increase the risk of infections. However, whether Ficus hirta Vahl. has effect on ammonia nitrogen stress is unclear. In present study we report that Ficus hirta Vahl. improves the activity of total antioxidant capacity (T-AOC), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) of shrimp and decreases shrimp mortality caused by ammonia nitrogen stress. It is demonstrated that miR-2765 is negatively regulate the antioxidant capacity. We find that SOD was a direct target gene of miR-2765. MiR-2765 can bind to 3′-untranslated region (3′-UTR) of SOD to inhibit its transcription. Furthermore, Ficus hirta Vahl. down-regulates miR-2765 to activate the antioxidant capacity to alleviate the damage caused by ammonia nitrogen stress. Interestingly, overexpression of miR-2765 could attenuate the protective effect of Ficus hirta Vahl. on shrimp under ammonia nitrogen stress. These data indicate that Ficus hirta Vahl. alleviates the damage of ammonia nitrogen stress in shrimp by repressing miR-2765 and activating the antioxidant enzyme system. This study will provide a theoretical basis and a new perspective for assessing the toxicity mechanism of ammonia nitrogen in the process of farming on shrimp.
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.
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.
Long noncoding RNAs (lncRNAs) have recently been recognized as the important regulators in cardiac diseases. This study was aimed to investigate the role and molecular mechanism of lncRNA KCNQ1OT1 in regulating cardiomyocyte apoptosis in heart failure (HF). The mouse model of HF was induced by doxorubicin (ADR). Cell apoptosis was detected by Hoechst and TUNEL staining. Molecule expressions were determined by qRT-PCR and western blot. The interaction between KCNQ1OT1 and Fused in sarcoma (FUS) was assessed by RNA immunoprecipitation (RIP) and RNA pull-down assay. KCNQ1OT1 was up-regulated in the myocardial tissues of HF mice and the ADR-stimulated mouse cardiomyocyte line (HL−1). KCNQ1OT1 overexpression promoted apoptosis of ADR-stimulated HL-1 cells, while KCNQ1OT1 knockdown caused the opposite effect. The RIP and RNA pull-down results showed that KCNQ1OT1 directly bound with FUS and negatively regulated its protein level. Knockdown of FUS inhibited apoptosis of ADR-stimulated HL-1 cells and reversed the effect of KCNQ1OT1 overexpression on cardiomyocyte apoptosis. In vivo experiment showed that KCNQ1OT1 improved myocardial histopathological changes, reduced myocardial fibrosis areas, down-regulated FUS expression, and inhibited cell apoptosis of HF mice. In conclusion, KCNQ1OT1 facilitates cardiomyocyte apoptosis by directly targeting FUS in ADR-induced HF.
Aging is characterized by the deterioration of different cellular and organismal structures and functions. A typical hallmark of the aging process is the accumulation of dysfunctional mitochondria and excess iron, leading to a vicious cycle that promotes cell and tissue damage, which ultimately contribute to organismal aging. Accordingly, altered mitochondrial quality control pathways such as mitochondrial autophagy (mitophagy) as well as altered iron homeostasis, with consequent iron overload, can accelerate the aging process and the development and progression of different age-associated disorders. In this review we first briefly introduce the aging process and summarize molecular mechanisms regulating mitophagy and iron homeostasis. We then provide an overview on how dysfunction of these two processes impact on aging and age-associated neurodegenerative disorders with a focus on Alzheimer’s disease, Parkinson’s disease and Amyotrophic Lateral Sclerosis. Finally, we summarize some recent evidence showing mechanistic links between iron metabolism and mitophagy and speculate on how regulating the crosstalk between the two processes may provide protective effects against aging and age-associated neuronal pathologies.
Objective: To determine the associations between plasma creatinine (PCr), plasma uric acid (PUA), and urinary oxidative stress (OS) biomarkers with the ALSFRS-R at baseline and survival in a large epidemiological cohort study (ALS COSMOS) with a well-phenotyped patient population (N = 355).
Methods: Fasting plasma and first void urine samples were obtained. PCr, PUA, urinary 8-oxo-deoxy guanosine (8-oxodG), and 15-F2t-isoprostane (IsoP) were analyzed at baseline, near the midpoint of follow-up, and at the final blood draw (before death or withdrawal from study). We estimated associations between these biomarkers and the ALSFRS-R at baseline and survival.
Results: At baseline, PCr correlated with ALSFRS-R (Spearman r = 0.30), percent (%) FVC (r = 0.20), PUA (r = 0.37), and 8-oxodG (r = −0.13, all p < 0.05). Baseline PCr significantly predicted survival (adjusted hazard ratio 0.28, p < 0.001). Time to death from baseline was shortest for those in the lowest two PCr quartiles relative to the highest two quartiles. PCr and ALSFRS-R values were significantly correlated at all three time points (baseline: r = 0.29, midpoint: r = 0.23, final: r = 0.38, all p < 0.001). PCr and PUA significantly declined over time, whereas OS biomarkers significantly increased over time.
Conclusions: To date, PCr predicted survival the best, compared to PUA, 8-oxodG, and IsoP. Although PCr represents the degree of muscle mass, it may also represent complex biochemical changes in ALS. Because the field has no reliable prognostic biomarkers, the importance of PCr warrants further investigation through clinical studies in ALS.
Amyotrophic lateral sclerosis (ALS) is a fatal late-onset neurodegenerative disease that specifically affects the function and survival of spinal and cortical motor neurons. ALS shares many genetic, clinical, and pathological characteristics with frontotemporal dementia (FTD), and these diseases are now recognized as presentations of a disease spectrum known as ALS/FTD. The molecular determinants of neuronal loss in ALS/FTD are still debated, but the recent discovery of nucleocytoplasmic transport defects as a common denominator of most if not all forms of ALS/FTD has dramatically changed our understanding of the pathogenic mechanisms of this disease. Loss of nuclear pores and nucleoporin aggregation, altered nuclear morphology, and impaired nuclear transport are some of the most prominent features that have been identified using a variety of animal, cellular, and human models of disease. Here, we review the experimental evidence linking nucleocytoplasmic transport defects to the pathogenesis of ALS/FTD and propose a unifying view on how these defects may lead to a vicious cycle that eventually causes neuronal death.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which pathogenesis and death of motor neurons are triggered by non-cell autonomous mechanisms. We showed earlier that exposing primary rat spinal cord cultures to conditioned media derived from primary mouse astrocyte conditioned media (ACM) that express human SOD1G93A (ACM-hSOD1G93A) quickly enhances Nav channel-mediated excitability and calcium influx, generates intracellular reactive oxygen species (ROS), and leads to death of motoneurons within days. Here we examined the role of mitochondrial structure and physiology and of the activation of c-Abl, a tyrosine kinase that induces apoptosis. We show that ACM-hSOD1G93A, but not ACM-hSOD1WT, increases c-Abl activity in motoneurons, interneurons and glial cells, starting at 60min; the c-Abl inhibitor STI571 (imatinib) prevents this ACM-hSOD1G93A-mediated motoneuron death. Interestingly, similar results were obtained with ACM derived from astrocytes expressing SOD1G86R or TDP43A315T. We further find that co-application of ACM-SOD1G93A with blockers of Nav channels (spermidine, mexiletine, or riluzole) or anti-oxidants (Trolox, esculetin, ortiron) effectively prevent c-Abl activation and motoneuron death. In addition, ACM-SOD1G93A induces alterations in the morphology of neuronal mitochondria that are related with their membrane depolarization. Finally, we find that blocking the opening of the mitochondrial permeability transition pore with cyclosporine A, or inhibiting mitochondrial calcium uptake with Ru360, reduces ROS production and c-Abl activation. Together, our data point to a sequence of events in which a toxic factor(s) released by ALS-expressing astrocytes rapidly induces hyper-excitability, which in turn increases calcium influx and affects mitochondrial structure and physiology. ROS production, mediated at least in part through mitochondrial alterations, trigger c-Abl signaling and lead to motoneuron death.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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Amyotrophic lateral sclerosis (ALS) is a fatal human neurodegenerative disease affecting primarily motor neurons. Two RNA-binding proteins, TDP-43 and FUS, aggregate in the degenerating motor neurons of ALS patients, and mutations in the genes encoding these proteins cause some forms of ALS. TDP-43 and FUS and several related RNA-binding proteins harbor aggregation-promoting prion-like domains that allow them to rapidly self-associate. This property is critical for the formation and dynamics of cellular ribonucleoprotein granules, the crucibles of RNA metabolism and homeostasis. Recent work connecting TDP-43 and FUS to stress granules has suggested how this cellular pathway, which involves protein aggregation as part of its normal function, might be coopted during disease pathogenesis.
Mutations in the gene encoding Fused in Sarcoma (FUS) cause amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. FUS is a predominantly nuclear DNA and RNA binding protein that is involved in RNA processing. Large FUS immuno-reactive inclusions fill the perikaryon of surviving motor neurons of ALS patients carrying mutations at post-mortem. This sequestration of FUS is predicted to disrupt RNA processing and initiate neurodegeneration. Here we demonstrate that C-terminal ALS mutations disrupt the nuclear localising signal (NLS) of FUS resulting in cytoplasmic accumulation in transfected cells and patient fibroblasts. FUS mislocalisation is rescued by the addition of the wild-type FUS NLS to mutant proteins. We also show that oxidative stress recruits mutant FUS to cytoplasmic stress granules where it is able to bind and sequester wild-type FUS. While FUS interacts with itself directly by protein-protein interaction, the recruitment of FUS to stress granules and interaction with PABP is RNA dependent. These findings support a two-hit hypothesis whereby cytoplasmic mislocalisation of FUS protein, followed by cellular stress contributes to the formation of cytoplasmic aggregates that may sequester FUS, disrupt RNA processing and initiate motor neuron degeneration.
FUS/TLS (fused in sarcoma/translocated in liposarcoma) and TDP-43 are integrally involved in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia. We found that FUS/TLS binds to RNAs from >5,500 genes in mouse and human brain, primarily through a GUGGU-binding motif. We identified a sawtooth-like binding pattern, consistent with co-transcriptional deposition of FUS/TLS. Depletion of FUS/TLS from the adult nervous system altered the levels or splicing of >950 mRNAs, most of which are distinct from RNAs dependent on TDP-43. Abundance of only 45 RNAs was reduced after depletion of either TDP-43 or FUS/TLS from mouse brain, but among these were mRNAs that were transcribed from genes with exceptionally long introns and that encode proteins that are essential for neuronal integrity. Expression levels of a subset of these were lowered after TDP-43 or FUS/TLS depletion in stem cell-derived human neurons and in TDP-43 aggregate-containing motor neurons in sporadic ALS, supporting a common loss-of-function pathway as one component underlying motor neuron death from misregulation of TDP-43 or FUS/TLS.
Cytoplasmic inclusions containing TAR DNA-binding protein of 43 kDa (TDP-43) or Fused in sarcoma (FUS) are a hallmark of amyotrophic lateral sclerosis (ALS) and several subtypes of frontotemporal lobar degeneration (FTLD). FUS-positive inclusions in FTLD and ALS patients are consistently co-labeled with stress granule (SG) marker proteins. Whether TDP-43 inclusions contain SG markers is currently still debated. We determined the requirements for SG recruitment of FUS and TDP-43 and found that cytoplasmic mislocalization is a common prerequisite for SG recruitment of FUS and TDP-43. For FUS, the arginine-glycine-glycine zinc finger domain, which is the protein's main RNA binding domain, is most important for SG recruitment, whereas the glycine-rich domain and RNA recognition motif (RRM) domain have a minor contribution and the glutamine-rich domain is dispensable. For TDP-43, both the RRM1 and the C-terminal glycine-rich domain are required for SG localization. ALS-associated point mutations located in the glycine-rich domain of TDP-43 do not affect SG recruitment. Interestingly, a 25-kDa C-terminal fragment of TDP-43, which is enriched in FTLD/ALS cortical inclusions but not spinal cord inclusions, fails to be recruited into SG. Consistently, inclusions in the cortex of FTLD patients, which are enriched for C-terminal fragments, are not co-labeled with the SG marker poly(A)-binding protein 1 (PABP-1), whereas inclusions in spinal cord, which contain full-length TDP-43, are frequently positive for this marker protein.
Background: Stress granules (SG) have been implicated in the formation of pathological FUS and TDP-43 inclusions.
Results: SG recruitment of FUS and TDP-43 requires cytosolic mislocalization and their main RNA binding domain and glycine-rich domain.
Conclusion: FUS and TDP-43 have similar requirements for SG recruitment.
Significance: Understanding how FUS and TDP-43 are recruited to SG is critical for understanding FTLD/ALS pathology.
Amyotrophic lateral sclerosis (ALS) is incurable and characterized by progressive paralysis of the muscles of the limbs, speech and swallowing, and respiration due to the progressive degeneration of voluntary motor neurons. Clinically indistinguishable ALS can be caused by genetic mutations of Cu/Zn superoxide