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)

Familial amyotrophic lateral sclerosis (FALS) is an autosomal dominant, adult onset, neurological disorder caused by the degeneration of motor neurons of the cortex, brainstem and spinal cord. Recently, the defective gene in some FALS families was identified as the Cu/Zn superoxide dismutase (SOD1) gene. However, SOD1 mutations are present in approximately 20% of patients with FALS. We have tested the genes of two more free radical detoxifying enzymes, Mn superoxide dismutase (SOD2) and catalase by single strand conformation analysis (SSCA) for mutations in the remaining FALS cases. No mutations were found in the catalase enzyme in 73 unrelated FALS cases; mutations were not detected in the 66% of the SOD2 gene analyzed. FALS does not appear to be caused by mutations in the SOD2 nor the catalase genes.
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PMID:Absence of mutations in the Mn superoxide dismutase or catalase genes in familial amyotrophic lateral sclerosis. 771 45

Recent studies have implicated free radicals in the pathogenesis of amyotrophic lateral sclerosis (ALS), a fatal, paralytic disorder of motor neurons. Herein we report on measurements of erythrocyte activity of the three main free radical scavenging enzymes: copper/zinc superoxide dismutase (Cu/Zn-SOD), catalase, and glutathione peroxidase. We studied 31 patients with sporadic ALS, 18 with familial ALS, and 24 controls, Mean Cu/Zn-SOD activity was reduced in eight familial ALS patients with mutations of Cu/Zn-SOD but was normal in patients with both familial ALS without identified Cu/Zn-SOD mutations and sporadic ALS. Glutathione peroxidase activity was significantly reduced only in sporadic ALS patients treated with insulin-like growth factor I (100 micrograms/kg). Catalase activity was normal in sporadic and familial ALS. Neither glutathione peroxidase nor catalase activities correlated significantly with duration of symptoms or age at onset. Vitamin E, vitamin C, and beta-carotene did not affect any of the three enzyme activities. These observations indicate that disturbances of catalase and glutathione peroxidase function are not likely to be central factors in the pathogenesis of ALS.
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PMID:Blood superoxide dismutase, catalase and glutathione peroxidase activities in familial and sporadic amyotrophic lateral sclerosis. 873 83

There is evidence of oxidative injury in postmortem brain, spinal cord, and CSF of patients with sporadic amyotrophic lateral sclerosis (SALS patients). We investigated the oxidative metabolism and calcium homeostasis in peripheral blood lymphocytes from such patients and did not find statistical differences in the basal oxygen consumption rate (QO2), cytochrome c oxidase activity, catalase activity, and lactate production. However the increase in QO2, induced by an uncoupler of oxidative phosphorylation, was depressed and the basal (resting) level of free cytosolic calcium ([Ca2+]in) was higher in lymphocytes from SALS patients (p < 0.01). Further increase in free [Ca2+]in challenged by a K+ channel blocker or by an uncoupler of oxidative phosphorylation was similar in SALS and control lymphocytes. The results show that systemic changes consistent with the presence of mitochondrial and of calcium metabolism dysfunction are present in SALS.
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PMID:Amyotrophic lateral sclerosis: oxidative energy metabolism and calcium homeostasis in peripheral blood lymphocytes. 885 45

Amyotrophic lateral sclerosis is a fatal paralytic disorder of unknown cause. Recent evidence implicated the role of free radicals in the death of motor neurons in this disease. To investigate this hypothesis further, we measured the activity of the main free radical scavenging enzymes copper/zinc superoxide dismutase, manganese superoxide dismutase, catalase, and glutathione peroxidase in postmortem brain samples from 9 patients with sporadic amyotrophic lateral sclerosis and from 9 control subjects. We examined samples from the precentral gyrus of the cerebral cortex, a region affected in amyotrophic lateral sclerosis, and from the cerebellar cortex, a region not affected. The two groups did not differ in age or postmortem delay. In the precentral gyrus from amyotrophic lateral sclerosis samples, glutathione peroxidase activity as measured by spectrophotometric assay (13.8 +/- 2.6 nmol/min/mg protein [mean +/- standard error of mean]) was reduced significantly compared to the activity in the precentral gyrus from control samples (22.7 +/- 0.5 nmol/min/mg protein). In contrast, glutathione peroxidase activity was not significantly altered in the cerebellar cortex from amyotrophic lateral sclerosis patients compared to controls. Copper/zinc superoxide dismutase, manganese superoxide dismutase (corrected or not corrected for citrate synthase), and catalase were not significantly altered in the precentral gyrus or cerebellar cortex in the patient samples. This study indicated that glutathione peroxidase activity is reduced in a brain region affected in amyotrophic lateral sclerosis, thus suggesting that free radicals may be implicated in the pathogenesis of the disease.
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PMID:Brain superoxide dismutase, catalase, and glutathione peroxidase activities in amyotrophic lateral sclerosis. 896 46

The activity of glutathione peroxidase (GSH-Px) as well as the activities of other antioxidative enzymes: CuZn superoxide dismutase (CuZn SOD), catalase (CAT), glutathione reductase (GR) in erythrocytes, as well as the activity of plasma glutathione transferase (GST), and the plasma content of vitamins E and C were evaluated in 35 sporadic amyotrophic lateral sclerosis (sALS) patients. The results revealed significantly decreased activity of both GSH-Px and CuZn SOD in sALS patients compared with the control. These data showed that a disturbed oxidative/antioxidative balance in sALS patients exists not only in motoneurons but also in the blood. The effect of exogenously administered selenium (Se), antioxidants, amino acids, a Ca2+ channel blocker such as nimodipine, and their combination in Alsamin was evaluated by screening parameter levels after 9 weeks of treatment. Only the use of all components together enhanced the activity of GSH-Px and the amount of vitamin E in sALS patients. Judging by the results of clinical trials, this treatment slowed the course of the disease.
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PMID:Glutathione peroxidase in amyotrophic lateral sclerosis: the effects of selenium supplementation. 972 10

Evidence is growing that reactive oxygen species (ROS), by-products of (normal) cellular aerobic metabolism, are involved in the pathogenesis of neurodegenerative diseases. One of these diseases is amyotrophic lateral sclerosis (ALS), in which motoneurons die, leading to paralysis and death. It remains uncertain whether ROS are the cause of (apoptotic) motoneuron death in ALS. To further understand the role of ROS in motoneuron death, we investigated the effects of ROS on isolated spinal rat motoneurons in culture. ROS were generated with a combination of iron(III) and ascorbate, or with hydrogen peroxide. Both toxic treatments resulted in a dose-dependent motoneuron death. Iron(III)/ascorbate toxicity was completely prevented with the hydrogen peroxide detoxifying enzyme catalase and partially prevented with the antioxidant vitamin E. SOD1, the enzyme that removes superoxide, did not protect against iron(III)/ascorbate toxicity. ROS treatment caused apoptotic motoneuron death: low doses of iron(III)/ ascorbate or hydrogen peroxide resulted in complete apoptosis ending in nuclear fragmentation, while high doses of ROS resulted in incomplete apoptosis (nuclear condensation). Thus, depending on the dose of ROS, the motoneurons complete the apoptotic pathway (low dose) or are stopped somewhere during this route (high dose).
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PMID:Oxidant treatment causes a dose-dependent phenotype of apoptosis in cultured motoneurons. 985 61

Mutations in the Cu/Zn-superoxide dismutase (SOD-1) gene underlie some familial cases of amyotrophic lateral sclerosis, a neurodegenerative disorder characterized by loss of cortical, brainstem, and spinal motor neurons. We present evidence that SOD-1 mutants alter the activity of molecular chaperones that aid in proper protein folding and targeting of abnormal proteins for degradation. In a cultured cell line (NIH 3T3), resistance to mutant SOD-1 toxicity correlated with increased overall chaperoning activity (measured by the ability of cytosolic extracts to prevent heat denaturation of catalase) as well as with up-regulation of individual chaperones/stress proteins. In transgenic mice expressing human SOD-1 with the G93A mutation, chaperoning activity was decreased in lumbar spinal cord but increased or unchanged in clinically unaffected tissues. Increasing the level of the stress-inducible chaperone 70-kDa heat shock protein by gene transfer reduced formation of mutant SOD-containing proteinaceous aggregates in cultured primary motor neurons expressing G93A SOD-1 and prolonged their survival. We propose that insufficiency of molecular chaperones may be directly involved in loss of motor neurons in this disease.
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PMID:Up-regulation of protein chaperones preserves viability of cells expressing toxic Cu/Zn-superoxide dismutase mutants associated with amyotrophic lateral sclerosis. 993 Jul 42

Alloxan (AL), a potent generator of superoxide and hydroxyl radicals, selectively destroys rodent pancreatic beta-cells. Alloxan-susceptible (ALS/Lt) and AL-resistant (ALR/Lt) are inbred mouse strains derived in Japan by inbreeding CD-1 (ICR) mice with concomitant selection for high or low sensitivity to a relatively low AL dose. The present study was undertaken to examine whether resistance was mediated by differences in either systemic or beta-cell antioxidant defense status. Superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPX) activities were determined in tissues of AL-untreated ALR/Lt and ALS/Lt male mice at 7 weeks of age. Specific activities of pancreatic SOD1, GR, and GPX were significantly increased in ALR/Lt mice compared with ALS/Lt mice. ALR/Lt mice further exhibited higher levels of glutathione in plasma, blood, pancreas, and liver combined with lower constitutive lipid peroxides in serum, liver, and pancreas. These results support the hypothesis that the selection process leading to the development of an AL-resistant mouse strain entailed accumulation of a gene or genes contributing to upregulated antioxidant status.
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PMID:Constitutive differences in antioxidant defense status distinguish alloxan-resistant and alloxan-susceptible mice. 1046 21

Dominant mutations in the copper/zinc superoxide dismutase (SOD1) gene have been observed in 15-20% of familial amyotrophic lateral sclerosis (FALS) cases. The mechanism by which SOD1 mutations result in motor neuron degeneration in FALS mice partly involves oxidative damage and an increased peroxidase activity of the mutant SOD1. A new therapeutic approach designed to eliminate the substrate of this peroxidase activity was examined in two lines of transgenic mice expressing the FALS-linked mutation glycine to alanine (G93A). We investigated the ability of putrescine-modified catalase (PUT-CAT), an antioxidant enzyme that removes hydrogen peroxide and has increased permeability at the blood-brain barrier, to modify the time course of the SOD1 mutation-induced motor neuron disease in these FALS mice. Continuous, subcutaneous administration of PUT-CAT significantly delayed the age at which onset of clinical disease occurred (indicated by loss of splay and/or tremors of hindlimbs) in a high-expressor line of FALS transgenic mice. Intraperitoneal injection of PUT-CAT given two times per week also significantly delayed the onset of clinical disease in a low-expressor line of FALS mice. PUT-CAT also significantly delayed the age at which clinical weakness developed (quantified by measuring the shortening of stride length) in both lines of FALS animals. No significant changes were observed in the survival times of the high-expressor FALS mice in any of the treatment groups. However, a trend toward a prolongation of survival was observed in the PUT-CAT-treated low-expressor FALS mice. These results support the role of free radical-mediated damage in the cascade of events leading to motor neurodegeneration in FALS and indicate that PUT-CAT interacts with a critical step in this cascade to delay the onset of clinical disease as well as the development of clinical weakness in FALS transgenic mice.
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PMID:Therapeutic benefits of putrescine-modified catalase in a transgenic mouse model of familial amyotrophic lateral sclerosis. 1048 88

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


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