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Drugs Jul 2023Tofersen (Qalsody) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was... (Review)
Review
Tofersen (Qalsody) is an antisense oligonucleotide being developed by Biogen for the treatment of amyotrophic lateral sclerosis (ALS). On 25 April 2023, tofersen was approved in the USA for the treatment of ALS in adults who have a mutation in the superoxide dismutase 1 (SOD1) gene. This article summarizes the milestones in the development of tofersen leading to this first approval for ALS.
Topics: Adult; Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Oligonucleotides; Superoxide Dismutase-1; Mutation
PubMed: 37316681
DOI: 10.1007/s40265-023-01904-6 -
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 -
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 -
International Journal of Molecular... Dec 2022Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the... (Review)
Review
Redox equilibria and the modulation of redox signalling play crucial roles in physiological processes. Overproduction of reactive oxygen species (ROS) disrupts the body's antioxidant defence, compromising redox homeostasis and increasing oxidative stress, leading to the development of several diseases. Manganese superoxide dismutase (MnSOD) is a principal antioxidant enzyme that protects cells from oxidative damage by converting superoxide anion radicals to hydrogen peroxide and oxygen in mitochondria. Systematic studies have demonstrated that MnSOD plays an indispensable role in multiple diseases. This review focuses on preclinical evidence that describes the mechanisms of MnSOD in diseases accompanied with an imbalanced redox status, including fibrotic diseases, inflammation, diabetes, vascular diseases, neurodegenerative diseases, and cancer. The potential therapeutic effects of MnSOD activators and MnSOD mimetics are also discussed. Targeting this specific superoxide anion radical scavenger may be a clinically beneficial strategy, and understanding the therapeutic role of MnSOD may provide a positive insight into preventing and treating related diseases.
Topics: Humans; Superoxides; Antioxidants; Superoxide Dismutase; Reactive Oxygen Species; Oxidation-Reduction; Oxidative Stress
PubMed: 36555531
DOI: 10.3390/ijms232415893 -
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 -
Oxidative Medicine and Cellular... 2022Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP).... (Review)
Review
Tardive dyskinesia (TD) is a prevalent movement disorder that significantly impacts patients with schizophrenia (SCZ) due to extended exposure to antipsychotics (AP). Several genetic polymorphisms, including superoxide dismutase (SOD) and DRD3 9ser, have been suggested as explanations why some patients suffer from TD. . A PubMed search was used to search relevant articles using the following keywords: "Tardive Dyskinesia and Superoxide Dismutase". Fifty-eight articles were retrieved. Among them, 16 were included in this review. . Overall, 58 studies were retrieved from PubMed. Most studies investigated the association between TD and the SOD-related polymorphisms. In addition, previous studies reported an association between TD occurrence and other genetic polymorphisms. . This study found that the risk of TD is associated with altered SOD levels and several genetic polymorphisms, including VAL 66 Met and DRD3 9ser.
Topics: Humans; Tardive Dyskinesia; Antipsychotic Agents; Polymorphism, Genetic; Schizophrenia; Superoxide Dismutase
PubMed: 36338339
DOI: 10.1155/2022/5748924 -
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 -
Brain : a Journal of Neurology Nov 2023The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the...
The current strategies to mitigate the toxicity of misfolded superoxide dismutase 1 (SOD1) in familial amyotrophic lateral sclerosis via blocking SOD1 expression in the CNS are indiscriminative for misfolded and intact proteins, and as such, entail a risk of depriving CNS cells of their essential antioxidant potential. As an alternative approach to neutralize misfolded and spare unaffected SOD1 species, we developed scFv-SE21 antibody that blocks the β6/β7 loop epitope exposed exclusively in misfolded SOD1. The β6/β7 loop epitope has previously been proposed to initiate amyloid-like aggregation of misfolded SOD1 and mediate its prion-like activity. The adeno-associated virus-mediated expression of scFv-SE21 in the CNS of hSOD1G37R mice rescued spinal motor neurons, reduced the accumulation of misfolded SOD1, decreased gliosis and thus delayed disease onset and extended survival by 90 days. The results provide evidence for the role of the exposed β6/β7 loop epitope in the mechanism of neurotoxic gain-of-function of misfolded SOD1 and open avenues for the development of mechanism-based anti-SOD1 therapeutics, whose selective targeting of misfolded SOD1 species may entail a reduced risk of collateral oxidative damage to the CNS.
Topics: Mice; Animals; Superoxide Dismutase-1; Amyotrophic Lateral Sclerosis; Superoxide Dismutase; Epitopes; Phenotype; Protein Folding; Disease Models, Animal; Mice, Transgenic
PubMed: 37394908
DOI: 10.1093/brain/awad222 -
Open Biology Jun 2021Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is... (Review)
Review
Oxidative stress, the imbalance of the antioxidant system, results in an accumulation of neurotoxic proteins in Alzheimer's disease (AD). The antioxidant system is composed of exogenous and endogenous antioxidants to maintain homeostasis. Superoxide dismutase (SOD) is an endogenous enzymatic antioxidant that converts superoxide ions to hydrogen peroxide in cells. SOD supplementation in mice prevented cognitive decline in stress-induced cells by reducing lipid peroxidation and maintaining neurogenesis in the hippocampus. Furthermore, SOD decreased expression of BACE1 while reducing plaque burden in the brain. Additionally, Astaxanthin (AST), a potent exogenous carotenoid, scavenges superoxide anion radicals. Mice treated with AST showed slower memory decline and decreased depositions of amyloid-beta (A) and tau protein. Currently, the neuroprotective potential of these supplements has only been examined separately in studies. However, a single antioxidant cannot sufficiently resist oxidative damage to the brain, therefore, a combinatory approach is proposed as a relevant therapy for ameliorating pathological changes in AD.
Topics: Alzheimer Disease; Animals; Antioxidants; Biomarkers; Clinical Studies as Topic; Dietary Supplements; Disease Management; Disease Susceptibility; Drug Evaluation, Preclinical; Humans; Neurons; Oxidative Stress; Reactive Oxygen Species; Superoxide Dismutase; Treatment Outcome; Xanthophylls
PubMed: 34186009
DOI: 10.1098/rsob.210013