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)

The discovery of missense mutations leading to reduced enzymatic activity in the copper/zinc superoxide dismutase (SOD1) in human familial amyotrophic lateral sclerosis has heightened interest in the role of free radicals in neurodegenerations but left the mechanisms by which they may cause neuronal death unexplained. We have approached this problem by specifically inhibiting the synthesis of SOD1 in cultured PC12 cells with antisense oligonucleotides. Cell survival in both untreated and nerve growth factor (NGF)-treated PC12 cells was inhibited by down-regulation of SOD1, with NGF-treated cells dying at lower levels of inhibition than untreated cells. Dying cells showed DNA degradation characteristic of apoptosis and could be rescued by the antioxidant vitamin E, with a combination of vitamin E and NGF being most efficacious. These results suggest that the induction of cell death by inhibition of SOD1 is due to free radical induction of apoptosis and that growth factor therapy for free-radical-mediated disease may require antioxidants in order to be effective.
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PMID:Down-regulation of copper/zinc superoxide dismutase causes apoptotic death in PC12 neuronal cells. 802 92

The cause of neuronal death in amyotrophic lateral sclerosis (ALS) is unknown. Recently, it was found that some patients with autosomal-dominant familial ALS (FALS) have point mutations in the gene that encodes Cu/Zn superoxide dismutase (SOD1). In this study of postmortem brain tissue, we examined SOD activity and quantified protein carbonyl groups, a marker of oxidative damage, in samples of frontal cortex (Brodmann area 6) from 10 control patients, three FALS patients with known SOD1 mutations (FALS-1), one autosomal-dominant FALS patient with no identifiable SOD1 mutations (FALS-O), and 11 sporadic ALS (SALS) patients. Also, we determined the activities of components of the electron transport chain (complexes I, II-III, and IV) in these samples. The cytosolic SOD activity, which is primarily SOD1 activity, was reduced by 38.8% (p < 0.05) in the FALS-1 patients and not significantly altered in the SALS patients or the FALS-O patient relative to the control patients. The mitochondrial SOD activity, which is primarily SOD2 activity, was not significantly altered in the FALS-1, FALS-O, or SALS patients. The protein carbonyl content was elevated by 84.8% (p < 0.01) in the SALS patients relative to the control patients. Finally, the complex I activity was increased by 55.3% (p < 0.001) in the FALS-1 patients relative to the control patients. These results from cortical tissue demonstrate that SOD1 activity is reduced and complex I activity is increased in FALS-1 patients and that oxidative damage to proteins is increased in SALS patients.
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PMID:Superoxide dismutase activity, oxidative damage, and mitochondrial energy metabolism in familial and sporadic amyotrophic lateral sclerosis. 824 85

Recent observations have suggested abnormalities in the gene for superoxide dismutase (SOD1) in patients with the familial form of amyotrophic lateral sclerosis (ALS). As SOD activity has secondary effects on glutathione (GSH), we have evaluated [35S]GSH binding in spinal cord sections from patients who died with sporadic ALS and control subjects. [35S]GSH binding sites were present in the grey matter of spinal cords in both the dorsal and ventral horns. ALS patients showed significantly increased [35S]GSH binding (+16%) in the dorsal and ventral grey horns compared to controls. Scatchard analysis of saturation binding data revealed that increased [35S]GSH binding was due to changes in the number rather than the affinity of GSH binding sites. These findings add support to a role for GSH in the mechanism loading to the pathogenesis of sporadic ALS.
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PMID:Increased [35S]glutathione binding sites in spinal cords from patients with sporadic amyotrophic lateral sclerosis. 829 42

Recent genetic analyses of patients with a familial, chromosome 21-linked form of amyotrophic lateral sclerosis (ALS), sometimes called Lou Gehrig's disease, suggest that mutations in the cytosolic copper/zinc superoxide dismutase (SOD1) gene may be involved in development of the disease. Although no functional disturbance of SOD1 activity has yet been identified, altered free radical protection may contribute to the destruction of motor neurons. The role of antioxidant status needs to be investigated as a possible preventive and therapeutic intervention for ALS.
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PMID:Mutations in the copper- and zinc-containing superoxide dismutase gene are associated with "Lou Gehrig's disease". 830 96

Oxidative stress has been implicated in the pathogenesis of several neurological disorders. We examined the regional distribution of copper/zinc superoxide dismutase (SOD-1), one of the key antioxidant enzymes, in the human central nervous system using in situ hybridization. Our results show that the enzyme is present at high levels of constitutive expression in alpha-motor neurons, oculomotor neurons, nucleus basalis, substantia nigra, neocortex, and the hippocampal sector resistant to hypoxia (H2). Relatively lower levels were found in Sommer's sector (H1) and Purkinje cells. We conclude that a lower constitutive level of SOD-1 expression may play a role in the selective vulnerability of certain neuronal populations to hypoxia but does not correlate with the patterns of neurodegeneration observed in amyotrophic lateral sclerosis. Parkinson's disease, and Alzheimer's disease.
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PMID:Copper/zinc superoxide dismutase expression in the human central nervous system. Correlation with selective neuronal vulnerability. 854 16

We studied serum concentrations of manganese superoxide dismutase (Mn SOD) and copper-zinc superoxide dismutase (Cu/Zn SOD) in 22 patients with polymyositis and dermatomyositis (PM/DM), 87 patients with four types of muscular dystrophy, 20 patients with amyotrophic lateral sclerosis, and 15 patients with collagen vascular diseases (CVD). Serum levels of Mn SOD were increased only in the patients with PM/DM and CVD, and the elevation was more prominent in those with PM/DM. Levels of Cu/Zn SOD were slightly elevated in some patients with PM/DM and Duchenne muscular dystrophy. In patients with PM/DM, the change in Mn SOD levels corresponded to disease activity as closely as or more closely than those of creatine kinase. The results indicate that serum Mn SOD may be a useful clinical marker for PM/DM.
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PMID:Elevated serum levels of manganese superoxide dismutase in polymyositis and dermatomyositis. 862 97

Although defects in the gene encoding the enzyme cytosolic copper/zinc superoxide dismutase (SOD1) have been reported in 20% of familial amyotrophic lateral sclerosis (ALS) patients, the etiology of the remaining familial cases and the more common sporadic form of the disease remains unknown. Recently, deletions of the neuronal apoptosis inhibitory protein gene NAIP, of the survival motor neuron gene SMN, and of a further cDNA fragment, XS2G3, have been reported in childhood-onset proximal spinal muscular atrophy (SMA), another disorder with pathology restricted to the motor system. We have therefore investigated the possibility of alterations in SMN and NAIP in 154 patients with ALS (135 sporadic cases, 17 familial cases). None of these patients revealed mutations in SMN by single-strand conformation polymorphism analysis. A single patient revealed a partial deletion of NAIP, with a homozygous absence of NAIP exon 5. While it is possible that this individual is one of the rare carriers of SMA who show NAIP deletions, a further explanation is that the NAIP deletion is in some way contributing to the ALS phenotype in this individual.
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PMID:Analysis of chromosome 5q13 genes in amyotrophic lateral sclerosis: homozygous NAIP deletion in a sporadic case. 865 52

Mutations of the copper/zinc superoxide dismutase (SOD-1) gene are present in around 20% of patients with a family history of amyotrophic lateral sclerosis. The finding of these mutations in patients with sporadic amyotrophic lateral sclerosis is rare. We describe a family with amyotrophic lateral sclerosis associated with the SOD-1 mutation Asp 101 Asn. This mutation was previously described as occurring in a patient with sporadic disease. We discuss the difficulties in defining truly sporadic amyotrophic lateral sclerosis, and the consequent implications on the neurogenetic advice given to other family members.
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PMID:Difficulties in distinguishing sporadic from familial amyotrophic lateral sclerosis. 865 56

The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
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PMID:Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. 867 2

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


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