Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Copper-zinc superoxide dismutase (Cu,ZnSOD) is the antioxidant enzyme that catalyzes the dismutation of superoxide (O2*-) to O2 and H2O2. In addition, Cu,ZnSOD also exhibits peroxidase activity in the presence of H2O2, leading to self-inactivation and formation of a potent enzyme-bound oxidant. We report in this study that lipid peroxidation of L-alpha-lecithin liposomes was enhanced greatly during the SOD/H2O2 reaction in the presence of nitrite anion (NO2-) with or without the metal ion chelator, diethylenetriaminepentacetic acid. The presence of NO2- also greatly enhanced alpha-tocopherol (alpha-TH) oxidation by SOD/H2O2 in saturated 1, 2-dilauroyl-sn-glycero-3-phosphatidylcholine liposomes. The major product identified by HPLC and UV-studies was alpha-tocopheryl quinone. When 1,2-diauroyl-sn-glycero-3-phosphatidylcholine liposomes containing gamma-tocopherol (gamma-TH) were incubated with SOD/H2O2/NO2-, the major product identified was 5-NO2-gamma-TH. Nitrone spin traps significantly inhibited the formation of alpha-tocopheryl quinone and 5-NO2-gamma-TH. NO2- inhibited H2O2-dependent inactivation of SOD. A proposed mechanism of this protection involves the oxidation of NO2- by an SOD-bound oxidant to the nitrogen dioxide radical (*NO2). In this study, we have shown a new mechanism of nitration catalyzed by the peroxidase activity of SOD. We conclude that NO2- is a suitable probe for investigating the peroxidase activity of familial Amyotrophic Lateral Sclerosis-linked SOD mutants.
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PMID:Nitration of gamma-tocopherol and oxidation of alpha-tocopherol by copper-zinc superoxide dismutase/H2O2/NO2-: role of nitrogen dioxide free radical. 978 14

In the CNS, reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemia-reperfusion injury, Alzheimer disease, Parkinson disease and aging. However, the exact mechanism is unknown, and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes, the most abundant glial cells in the brain. We examined hydrogen peroxide (H2O2)-induced DNA fragmentation and thymidine incorporation into cultured astrocytes as an indicator of the process of recovery from astrocytic DNA injury. Astrocytes were isolated from cerebral cortices of 0-day-old rats and treated with 1 mM dibutyryl cyclic AMP for 4 days. H2O2 of 100 microM stimulated thymidine incorporation into astrocytes. Caffeine, ryanodine, cyclic ADP-ribose (endogenous ryanodine receptor agonist) and beta-NAD+ (precursor of cyclic ADP-ribose) suppressed partially the stimulatory effect of H2O2. Ruthenium red (ryanodine receptor antagonist) facilitated further the stimulatory effect of H2O2. The facilitated effect of ruthenium red on H2O2-induced thymidine incorporation was suppressed by caffeine, ryanodine, cyclic ADP-ribose and beta-NAD+. H2O2-induced DNA fragmentation and astrocytic death were suppressed by ruthenium red. These findings suggest that the process of recovery from astrocytic DNA injury by H2O2 may be regulated by Ca2+ efflux from ryanodine-sensitive intracellular Ca2+ stores.
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PMID:[Role of ryanodine receptors in hydrogen peroxide-induced DNA fragmentation and thymidine incorporation in cultured rat astrocytes]. 1019 Jan 45

In this study, we examined the effects of oxidative stress on a nitric oxide (NO)-regulated neuroendocrine function, the release of arginine vasopressin (AVP) by the hypothalamo-neurohypophyseal axis. Treatment of mouse-isolated hypothalami and neurointermediate lobes (NIL) with H2O2 increased AVP release. This effect was inhibited by copper-zinc superoxide dismutase-1 (SOD1) analogs. By measuring cGMP accumulation as an indicator of biologically active NO, we found that H2O2 treatment decreased cGMP formation in both hypothalami and NIL. We have previously shown that NO inhibits AVP release by a cGMP-independent mechanism. Given that H2O2 stimulated AVP release, while it reduced cGMP production, our findings strongly suggest that oxidative damage affects neurosecretion by reducing NO availability. To test whether such a mechanism may operate under pathological conditions with pronounced oxidative stress, we compared neurosecretion in wild-type and transgenic mice carrying a mutated form of SOD1 associated with human familial amyotrophic lateral sclerosis. Reminiscent of the data obtained from H2O2-treated tissues, hypothalami and NIL from SOD1 mutants displayed decreased cGMP accumulation and increased AVP release, compared with tissues from wild-type littermates. Since neuronal NO synthase expression was not modified, we conclude that the perturbed free radical metabolism associated with the SOD1 mutation is likely to trap NO, and thereby alter neurosecretion, a mechanism that can be exacerbated in specific physiopathological conditions.
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PMID:Oxidative stress and a murine superoxide dismutase-1 mutation promoting amyotrophic lateral sclerosis alter neurosecretion in the hypothalamo-neurohypophyseal axis. 1034 79

Oxidative stress is believed to play a central role in the pathogenesis of amyotrophic lateral sclerosis (ALS). We investigated the protective effects of overexpression of catalase in primary cultures of rat spinal motoneurons against the oxidative stress of hydrogen peroxide. Using microinjection, catalase-encoding cDNA was transferred into the motoneurons. In another approach, motoneurons were injected with a catalase solution. Both procedures elevated the intracellular antioxidant status of the cultured motoneurons as evidenced by a significant protection against H2O2 toxicity. We conclude that modulating the expression of enzymes involved in cellular defense against oxidative stress can render cells more resistant to oxidant toxicity.
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PMID:Microinjection of catalase cDNA prevents hydrogen peroxide-induced motoneuron death. 1057 85

Glutathione deficiency has been associated with a number of neurodegenerative diseases including Lou Gehrig's disease, Parkinson's disease, and HIV. A crucial role for glutathione is as a free radical scavenger. Alzheimer's disease (AD) brain is characterized by oxidative stress, manifested by protein oxidation, lipid oxidation, oxidized glutathione, and decreased activity of glutathione S-transferase, among others. Reasoning that elevated levels of endogenous glutathione would offer protection against free radical-induced oxidative stress, rodents were given in vivo injections of N-acetylcysteine (NAC), a known precursor of glutathione, to study the vulnerability of isolated synaptosomal membranes treated with Fe2+/H2O2, a known hydroxyl free radical producer. Protein carbonyls, a marker of protein oxidation, were measured. NAC significantly increased endogenous glutathione levels in cortical synaptosome cytosol (P < 0.01). As reported previously, protein carbonyl levels of the Fe2+/H2O2-treated synaptosomes were significantly higher compared to that of non-treated controls (P < 0.01), consistent with increased oxidative stress. In contrast, protein carbonyl levels in Fe2+/H2O2-treated synaptosomes isolated from NAC-injected animals were not significantly different from saline-injected non-treated controls, demonstrating protection against hydroxyl radical induced oxidative stress. These results are consistent with the notion that methods to increase endogenous glutathione levels in neurodegenerative diseases associated with oxidative stress, including AD, may be promising.
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PMID:In-vivo glutathione elevation protects against hydroxyl free radical-induced protein oxidation in rat brain. 1067 51

Nuclear factor kappa B (NF-kappa B) is a transcription factor crucially involved in glial and neuronal function. NF-kappa B is ubiquitously distributed within the nervous system, and its inducible activity can be discerned from constitutive activity. Prototypic inducible NF-kappa B in the nervous system is composed of the DNA-binding subunits p50 and p65 complexed with an inhibitory I kappa B-alpha molecule. A number of signals from the cell surface can lead to rapid activation of NK-kappa B, thus releasing the inhibition by I kappa B. This activates translocation of NF-kappa B to the nucleus, where it binds to kappa B motifs of target genes and activates transcription. Previous findings have identified reactive oxygen intermediates (ROI) as a common denominator of NF-kappa B activating signals. More specifically, hydrogen peroxide (H2O2) might be used as second messenger in the NF-kappa B system, despite its cytotoxicity. Analysis of pathways leading to NF-kappa B activation in the nervous system has identified a number of ROI-dependent pathways such as cytokine- and neurotrophin-mediated activation, glutamatergic signal transduction, and various diseases with crucial ROI involvement (e.g., Alzheimer's disease, Parkinson's disease, experimental autoimmune encephalomyelitis, multiple sclerosis, amyotrophic lateral sclerosis, and injury). A number of NF-kappa B-specific target genes contribute to the production of ROI or are involved in detoxification of ROIs. In this review, possible mechanisms and regulatory pathways of ROI-mediated NF-kappa B activation are discussed.
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PMID:Activation of NF-kappa B by reactive oxygen intermediates in the nervous system. 1122 42

Mutations in Cu/Zn-superoxide dismutase (SOD1) are associated with some cases of familial amyotrophic lateral sclerosis (ALS). We overexpressed Bcl-2, wild-type SOD1 or mutant SOD1s (G37R and G85R) in NT-2 and SK-N-MC cells. Overexpression of Bcl-2 rendered cells more resistant to apoptosis induced by serum withdrawal, H2O2 or 4-hydroxy-2-trans-nonenal (HNE). Overexpression of Bcl-2 had little effect on levels of protein carbonyls, lipid peroxidation, 8-hydroxyguanine (8-OHG) or 3-nitrotyrosine. Serum withdrawal or H2O2 raised levels of protein carbonyls, lipid peroxidation, 8-OHG and 3-nitrotyrosine, changes that were attenuated in cells overexpressing Bcl-2. Overexpression of either SOD1 mutant tended to increase levels of lipid peroxidation, protein carbonyls, and 3-nitrotyrosine and accelerated viability loss induced by serum withdrawal, H2O2 or HNE, accompanied by greater rises in oxidative damage parameters. The effects of mutant SOD1s were attenuated by Bcl-2. By contrast, expression of wild-type SOD1 rendered cells more resistant to loss of viability induced by serum deprivation, HNE or H2O2. The levels of lipid peroxidation in wild-type SOD1 transfectants were elevated. Overexpression of mutant SOD1s makes cells more predisposed to undergo apoptosis in response to several insults. Our cellular systems appear to mimic events in patients with ALS or transgenic mice overexpressing mutant SOD1.
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PMID:Effect of overexpression of wild-type and mutant Cu/Zn-superoxide dismutases on oxidative stress and cell death induced by hydrogen peroxide, 4-hydroxynonenal or serum deprivation: potentiation of injury by ALS-related mutant superoxide dismutases and protection by Bcl-2. 1146 56

Mutations in Cu,Zn superoxide dismutase (Cu,Zn SOD) account for approximately 20% of cases of familial amyotrophic lateral sclerosis (ALS), a late-onset neurodegenerative disease affecting motor neurons. These mutations decrease protein stability and lower zinc affinity. Zinc-deficient SOD (Cu,E SOD) has altered redox activities and is toxic to motor neurons in vitro. Using bovine SOD, we studied the effects of hydrogen peroxide (H(2)O(2)) on Cu,E SOD and Cu,Zn SOD. Hydrogen peroxide treatment of Cu,E SOD inactivated zinc binding activity six times faster than superoxide dismutase activity, whereas inactivation of dismutase activity occurred at the same rate for both Cu,Zn SOD and Cu,E SOD. Zinc binding by Cu,E SOD was also damaged by simultaneous generation of superoxide and hydrogen peroxide by xanthine oxidase plus xanthine. Although urate, xanthine, and ascorbate can protect superoxide dismutase activity of Cu,Zn SOD from inactivation, they were not effective at protecting Cu,E SOD. Hydrogen peroxide induced subtle changes in the tertiary structure but not the secondary structure of Cu,E SOD as detected by near and far UV circular dichroism. Our results suggest that low levels of hydrogen peroxide could potentially enhance the toxicity of zinc deficient SOD to motor neurons in ALS by rendering zinc loss from SOD irreversible.
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PMID:Hydrogen peroxide damages the zinc-binding site of zinc-deficient Cu,Zn superoxide dismutase. 1146 88

Aggregates of Cu/Zn superoxide dismutase (SOD) have been demonstrated in familial amyotrophic lateral sclerosis (FALS) and other neurodegenerative diseases; however, their role in disease pathogenesis is unclear. In this study, we investigated the presence of SOD aggregates in nerve growth factor (NGF)-differentiated PC12 cells and cell viability following: (i) transduction with replication-deficient recombinant adenoviruses (AdVs) expressing wild-type SOD (SODWT) or mutant SOD (SODMT, V148G or A4V); (ii) transfection of yellow fluorescent protein-tagged SODWT (SODWT-YFP) or SODMT (SODA4V-YFP, SODV148G-YFP). SOD aggregates were more prominent in cells following transduction of AdSODMT than AdSODWT and following treatment with H2O2, suggesting that mutant SOD leads to oxidation of cellular components. In addition, cells expressing SODMT-YFP yielded SOD aggregates that were significantly larger and more frequent than SOD aggregates in cells expressing SODWT-YFP. Proteasome inhibitors, but not cathepsin B inhibitors, increased aggregate formation but did not increase cell death. In addition, treatments that increased cell viability did not significantly decrease SOD aggregates. Taken together, our data demonstrate that there is no association between SOD aggregates and cell death in FALS.
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PMID:No correlation between aggregates of Cu/Zn superoxide dismutase and cell death in familial amyotrophic lateral sclerosis. 1235 70

Hydrogen peroxide can interact with the active site of copper-zinc superoxide dismutase (SOD1) to generate a powerful oxidant. This oxidant can either damage amino acid residues at the active site, inactivating the enzyme (the self-oxidative pathway), or oxidize substrates exogenous to the active site, preventing inactivation (the external oxidative pathway). It is well established that the presence of bicarbonate anion dramatically enhances the rate of oxidation of exogenous substrates. Here, we show that bicarbonate also substantially enhances the rate of self-inactivation of human wild type SOD1. Together, these observations suggest that the strong oxidant formed by hydrogen peroxide and SOD1 in the presence of bicarbonate arises from a pathway mechanistically distinct from that producing the oxidant in its absence. Self-inactivation rates are further enhanced in a mutant SOD1 protein (L38V) linked to the fatal neurodegenerative disorder, familial amyotrophic lateral sclerosis. The 1.4 A resolution crystal structure of pathogenic SOD1 mutant D125H reveals the mode of oxyanion binding in the active site channel and implies that phosphate anion attenuates the bicarbonate effect by competing for binding to this site. The orientation of the enzyme-associated oxyanion suggests that both the self-oxidative and external oxidative pathways can proceed through an enzyme-associated peroxycarbonate intermediate.
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PMID:An alternative mechanism of bicarbonate-mediated peroxidation by copper-zinc superoxide dismutase: rates enhanced via proposed enzyme-associated peroxycarbonate intermediate. 1264 72


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