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Gene Feb 2016Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neural disorder that causes death of the motor neurons in the brain and spinal cord; this affects the voluntary muscles and gradually leads to paralysis of the whole body. Most ALS cases are sporadic, though about 5-10% are familial. ALS is caused by multiple factors including mutation in any one of a number of specific genes, one of the most frequently affected is superoxide dismutase (SOD) 1. Alterations in SOD 1 have been linked with several variants of familial ALS. SOD 1 is a powerful antioxidant enzyme that protects cells from the damaging effects of superoxide radicals. The enzyme binds both copper and zinc ions that are directly involved in the deactivation of toxic superoxide radicals. Mutated SOD1 gene can acquire both gain and loss of function mutations. The most commonly identified mutations in SOD1 that affect protein activity are D90A, A4V and G93A. Deleterious mutations have been shown to modify SOD1 activity, which leads to the accumulation of highly toxic hydroxyl radicals. Accumulation of these free radicals causes degradation of both nuclear and mitochondrial DNA and protein misfolding, features which can be used as pathological indicators associated with ALS. Numerous clinical trials have been carried out over last few years with limited success. In some patients advanced techniques like gene and stem cell therapy have been trialed. However no definitive treatment option can provide a cure and currently ALS is managed by drugs and other supportive therapies. Consequently there is a need to identify new approaches for treatment of this ultimately fatal disease.
Topics: Amino Acid Sequence; Amyotrophic Lateral Sclerosis; Animals; Genetic Therapy; Humans; Molecular Sequence Data; Mutation; Reactive Oxygen Species; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 26657039
DOI: 10.1016/j.gene.2015.11.049 -
The Journal of Cell Biology Jun 2018Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen... (Review)
Review
Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling.
Topics: Animals; Disease; Humans; Models, Animal; Oxidation-Reduction; Reactive Oxygen Species; Signal Transduction; Superoxide Dismutase
PubMed: 29669742
DOI: 10.1083/jcb.201708007 -
Advances in Neurobiology 2022Motoneuron diseases (MNDs) represent a heterogeneous group of progressive paralytic disorders, mainly characterized by the loss of upper (corticospinal) motoneurons,...
Motoneuron diseases (MNDs) represent a heterogeneous group of progressive paralytic disorders, mainly characterized by the loss of upper (corticospinal) motoneurons, lower (spinal) motoneurons or, often both. MNDs can occur from birth to adulthood and have a highly variable clinical presentation, even within gene-positive forms, suggesting the existence of environmental and genetic modifiers. A combination of cell autonomous and non-cell autonomous mechanisms contributes to motoneuron degeneration in MNDs, suggesting multifactorial pathogenic processes.
Topics: Adult; Amyotrophic Lateral Sclerosis; Humans; Motor Neuron Disease; Motor Neurons; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 36066831
DOI: 10.1007/978-3-031-07167-6_13 -
The Neuroscientist : a Review Journal... Oct 2015The canonical role of superoxide dismutase 1 (SOD1) is as an antioxidant enzyme protecting the cell from reactive oxygen species toxicity. SOD1 was also the first gene... (Review)
Review
The canonical role of superoxide dismutase 1 (SOD1) is as an antioxidant enzyme protecting the cell from reactive oxygen species toxicity. SOD1 was also the first gene in which mutations were found to be causative for the neurodegenerative disease amyotrophic lateral sclerosis (ALS), more than 20 years ago. ALS is a relentless and incurable mid-life onset disease, which starts with a progressive paralysis and usually leads to death within 3 to 5 years of diagnosis; in the majority of cases, the intellect appears to remain intact while the motor system degenerates. It rapidly became clear that when mutated SOD1 takes on a toxic gain of function in ALS. However, this novel function remains unknown and many cellular systems have been implicated in disease. Now it seems that SOD1 may play a rather larger role in the cell than originally realized, including as a key modulator of glucose signaling (at least so far in yeast) and in RNA binding. Here, we consider some of the new findings for SOD1 in health and disease, which may shed light on how single amino acid changes at sites throughout this protein can cause devastating neurodegeneration in the mammalian motor system.
Topics: Amyotrophic Lateral Sclerosis; Animals; Endoplasmic Reticulum; Humans; Mutation; RNA; Reactive Oxygen Species; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 25492944
DOI: 10.1177/1073858414561795 -
Cell Death and Differentiation Jun 2022Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s)...
Amyotrophic lateral sclerosis (ALS) is caused by selective degeneration of motor neurons in the brain and spinal cord; however, the primary cell death pathway(s) mediating motor neuron demise remain elusive. We recently established that necroptosis, an inflammatory form of regulated cell death, was dispensable for motor neuron death in a mouse model of ALS, implicating other forms of cell death. Here, we confirm these findings in ALS patients, showing a lack of expression of key necroptotic effector proteins in spinal cords. Rather, we uncover evidence for ferroptosis, a recently discovered iron-dependent form of regulated cell death, in ALS. Depletion of glutathione peroxidase 4 (GPX4), an anti-oxidant enzyme and central repressor of ferroptosis, occurred in post-mortem spinal cords of both sporadic and familial ALS patients. GPX4 depletion was also an early and universal feature of spinal cords and brains of transgenic mutant superoxide dismutase 1 (SOD1), TDP-43 and C9orf72 mouse models of ALS. GPX4 depletion and ferroptosis were linked to impaired NRF2 signalling and dysregulation of glutathione synthesis and iron-binding proteins. Novel BAC transgenic mice overexpressing human GPX4 exhibited high GPX4 expression localised to spinal motor neurons. Human GPX4 overexpression in SOD1 mice significantly delayed disease onset, improved locomotor function and prolonged lifespan, which was attributed to attenuated lipid peroxidation and motor neuron preservation. Our study discovers a new role for ferroptosis in mediating motor neuron death in ALS, supporting the use of anti-ferroptotic therapeutic strategies, such as GPX4 pathway induction and upregulation, for ALS treatment.
Topics: Amyotrophic Lateral Sclerosis; Animals; Cell Death; Disease Models, Animal; Ferroptosis; Humans; Mice; Mice, Transgenic; Motor Neurons; Spinal Cord; Superoxide Dismutase; Superoxide Dismutase-1
PubMed: 34857917
DOI: 10.1038/s41418-021-00910-z -
Cellular and Molecular Neurobiology Nov 2023Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons... (Review)
Review
Amyotrophic Lateral Sclerosis (ALS) is one of the commonest neurodegenerative diseases of adult-onset, which is characterized by the progressive death of motor neurons in the cerebral cortex, brain stem and spinal cord. The dysfunction and death of motor neurons lead to the progressive muscle weakness, atrophy, fasciculations, spasticity and ultimately the whole paralysis of body. Despite the identification of several genetic mutations associated with the pathogenesis of ALS, including mutations in chromosome 9 open reading frame 72 leading to the abnormal expansion of GGGGCC repeat sequence, TAR DNA-binding protein 43, fused in sarcoma/translocated in liposarcoma, copper/zinc superoxide dismutase 1 (SOD1) and TANK-binding kinase 1, the exact mechanisms underlying the specific degeneration of motor neurons that causes ALS remain incompletely understood. At present, since the transgenic model expressed SOD1 mutants was established, multiple in vitro models of ALS have been developed for studying the pathology, pathophysiology and pathogenesis of ALS as well as searching the effective neurotherapeutics. This review reviewed the details of present established in vitro models used in studying the pathology, pathophysiology and pathogenesis of ALS. Meanwhile, we also discussed the advantages, disadvantages, cost and availability of each models.
Topics: Animals; Humans; Mice; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Disease Models, Animal; Motor Neurons; Mutation; Superoxide Dismutase; Mice, Transgenic
PubMed: 37870685
DOI: 10.1007/s10571-023-01423-8 -
Advances in Clinical Chemistry 2015Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and antioxidant defenses. Two main antioxidant systems exist. The nonenzymatic... (Review)
Review
Oxidative stress is characterized by imbalanced reactive oxygen species (ROS) production and antioxidant defenses. Two main antioxidant systems exist. The nonenzymatic system relies on molecules to directly quench ROS and the enzymatic system is composed of specific enzymes that detoxify ROS. Among the latter, the superoxide dismutase (SOD) family is important in oxidative stress modulation. Of these, manganese-dependent SOD (MnSOD) plays a major role due to its mitochondrial location, i.e., the main site of superoxide (O(2)(·-)) production. As such, extensive research has focused on its capacity to modulate oxidative stress. Early data demonstrated the relevance of MnSOD as an O(2)(·-) scavenger. More recent research has, however, identified a prominent role for MnSOD in carcinogenesis. In addition, SOD downregulation appears associated with health risk in heart and brain. A single nucleotide polymorphism which alters the mitochondria signaling sequence for the cytosolic MnSOD form has been identified. Transport into the mitochondria was differentially affected by allelic presence and a new chapter in MnSOD research thus begun. As a result, an ever-increasing number of diseases appear associated with this allelic variation including metabolic and cardiovascular disease. Although diet and exercise upregulate MnSOD, the relationship between environmental and genetic factors remains unclear.
Topics: Exercise; Humans; Oxidative Stress; Polymorphism, Single Nucleotide; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 25858870
DOI: 10.1016/bs.acc.2014.11.001 -
Proceedings of the National Academy of... Jan 2023Although hydrogen sulfide (HS) is an endogenous signaling molecule with antioxidant properties, it is also cytotoxic by potently inhibiting cytochrome c oxidase and...
Although hydrogen sulfide (HS) is an endogenous signaling molecule with antioxidant properties, it is also cytotoxic by potently inhibiting cytochrome c oxidase and mitochondrial respiration. Paradoxically, the primary route of HS detoxification is thought to occur inside the mitochondrial matrix a series of relatively slow enzymatic reactions that are unlikely to compete with its rapid inhibition of cytochrome c oxidase. Therefore, alternative or complementary cellular mechanisms of HS detoxification are predicted to exist. Here, superoxide dismutase [Cu-Zn] (SOD1) is shown to be an efficient HS oxidase that has an essential role in limiting cytotoxicity from endogenous and exogenous sulfide. Decreased SOD1 expression resulted in increased sensitivity to HS toxicity in yeast and human cells, while increased SOD1 expression enhanced tolerance to HS. SOD1 rapidly converted HS to sulfate under conditions of limiting sulfide; however, when sulfide was in molar excess, SOD1 catalyzed the formation of per- and polysulfides, which induce cellular thiol oxidation. Furthermore, in SOD1-deficient cells, elevated levels of reactive oxygen species catalyzed sulfide oxidation to per- and polysulfides. These data reveal that a fundamental function of SOD1 is to regulate HS and related reactive sulfur species.
Topics: Humans; Electron Transport Complex IV; Hydrogen Sulfide; Sulfides; Superoxide Dismutase; Superoxide Dismutase-1; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins
PubMed: 36630448
DOI: 10.1073/pnas.2205044120 -
Proceedings of the National Academy of... Dec 2021Cytoglobin (Cygb) was discovered as a novel type of globin that is expressed in mammals; however, its functions remain uncertain. While Cygb protects against oxidant...
Cytoglobin (Cygb) was discovered as a novel type of globin that is expressed in mammals; however, its functions remain uncertain. While Cygb protects against oxidant stress, the basis for this is unclear, and the effect of Cygb on superoxide metabolism is unknown. From dose-dependent studies of the effect of Cygb on superoxide catabolism, we identify that Cygb has potent superoxide dismutase (SOD) function. Initial assays using cytochrome showed that Cygb exhibits a high rate of superoxide dismutation on the order of 10 M ⋅ s Spin-trapping studies also demonstrated that the rate of Cygb-mediated superoxide dismutation (1.6 × 10 M ⋅ s) was only ∼10-fold less than Cu,Zn-SOD. Stopped-flow experiments confirmed that Cygb rapidly dismutates superoxide with rates within an order of magnitude of Cu,Zn-SOD or Mn-SOD. The SOD function of Cygb was inhibited by cyanide and CO that coordinate to Fe-Cygb and Fe-Cygb, respectively, suggesting that dismutation involves iron redox cycling, and this was confirmed by spectrophotometric titrations. In control smooth-muscle cells and cells with siRNA-mediated Cygb knockdown subjected to extracellular superoxide stress from xanthine/xanthine oxidase or intracellular superoxide stress triggered by the uncoupler, menadione, Cygb had a prominent role in superoxide metabolism and protected against superoxide-mediated death. Similar experiments in vessels showed higher levels of superoxide in mice than wild type. Thus, Cygb has potent SOD function and can rapidly dismutate superoxide in cells, conferring protection against oxidant injury. In view of its ubiquitous cellular expression at micromolar concentrations in smooth-muscle and other cells, Cygb can play an important role in cellular superoxide metabolism.
Topics: Animals; Cell Line; Cytoglobin; Electron Spin Resonance Spectroscopy; Male; Mice; Mice, Knockout; Reactive Oxygen Species; Superoxide Dismutase
PubMed: 34930834
DOI: 10.1073/pnas.2105053118 -
Current Topics in Medicinal Chemistry 2017In recent years, several scientific investigations have reported the therapeutic implications of superoxide dismutase (SOD) against oxidative stress and -induced... (Review)
Review
In recent years, several scientific investigations have reported the therapeutic implications of superoxide dismutase (SOD) against oxidative stress and -induced pathology in clinical and preclinical trials. Indeed, various kinase, molecular signaling and physiological process has altered by reactive oxygen species. In spite of the abundant available literature reports, patents, clinical trials and commercialized products, the therapeutic application of SOD as a potential drug still remains unclear. Owing to the technical challenges associated with the utilization of SOD as a drug, we revisited the structural arrangement and cellular signaling, significant association with kinase, exploring the new target sites and introducing new formulation strategies such as gene modulation, nano-formulations and click chemistry is a prerequisite. In-addition to gene modulation strategies, encapsulated formulation within a nano-carrier for producing promising SOD therapeutic effects, application of click chemistry including bioconjugation and cyclo-addition are the most prominent methods to produce highly efficient SOD formulations. Thus, the present review enlightens the foremost technique which may have better interaction with kinase and other cellular signaling for regulating the physiological process.
Topics: Animals; Drug Discovery; Humans; Oxidative Stress; Protein Kinase Inhibitors; Protein Kinases; Signal Transduction; Superoxide Dismutase
PubMed: 28270086
DOI: 10.2174/1568026617666170307112837