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)

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

Dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase have been found in members of certain families with familial amyotrophic lateral sclerosis (ALS). To better understand the contribution of SOD1 mutations in the pathogenesis of familial ALS, we developed transgenic mice expressing one of the mutations found in familial ALS. These animals display clinical and pathological features closely resembling human ALS. Early changes observed in these animals were intra-axonal and dendritic vacuoles due to dilatation of the endoplasmic reticulum and vacuolar degeneration of mitochondria. We have reported that the Golgi apparatus of spinal cord motor neurons in patients with sporadic ALS is fragmented and atrophic. In this study we show that spinal cord motor neurons of transgenic mice for an SOD1 mutation display a lesion of the Golgi apparatus identical to that found in humans with sporadic ALS. In these mice, the stacks of the cisternae of the fragmented Golgi apparatus are shorter than in the normal organelle, and there is a reduction in Golgi-associated vesicles and adjacent cisternae of the rough endoplasmic reticulum. Furthermore, the fragmentation of the Golgi apparatus occurs in an early, presymptomatic stage and usually precedes the development of the vacuolar changes. Transgenic mice overexpressing the wild-type human superoxide dismutase are normal. In familial ALS, an early lesion of the Golgi apparatus of motor neurons may have adverse functional effects, because newly synthesized proteins destined for fast axoplasmic transport pass through the Golgi apparatus.
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PMID:The Golgi apparatus of spinal cord motor neurons in transgenic mice expressing mutant Cu,Zn superoxide dismutase becomes fragmented in early, preclinical stages of the disease. 864 99

Cu,Zn-superoxide dismutase (SOD) is known to be a locus of mutation in familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express a mutant Cu,Zn-SOD, Gly-93--> Ala (G93A), have been shown to develop amyotrophic lateral sclerosis (ALS) symptoms. We cloned the FALS mutant, G93A, and wild-type cDNA of human Cu,Zn-SOD, overexpressed them in Sf9 insect cells, purified the proteins, and studied their enzymic activities for catalyzing the dismutation of superoxide anions and the generation of free radicals with H2O2 as substrate. Our results showed that both enzymes contain one copper ion per subunit and have identical dismutation activity. However, the free radical-generating function of the G93A mutant, as measured by the spin trapping method, is enhanced relative to that of the wild-type enzyme, particularly at lower H2O2 concentrations. This is due to a small, but reproducible, decrease in the value of Km for H2O2 for the G93A mutant, while the kcat is identical for both enzymes. Thus, the ALS symptoms observed in G93A transgenic mice are not caused by the reduction of Cu,Zn-SOD activity with the mutant enzyme; rather, it is induced by a gain-of-function, an enhancement of the free radical-generating function. This is consistent with the x-ray crystallographic studies showing the active channel of the FALS mutant is slightly larger than that of the wild-type enzyme; thus, it is more accessible to H2O2. This gain-of-function, in part, may provide an explanation for the association between ALS and Cu,Zn-SOD mutants.
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PMID:A gain-of-function of an amyotrophic lateral sclerosis-associated Cu,Zn-superoxide dismutase mutant: An enhancement of free radical formation due to a decrease in Km for hydrogen peroxide. 865 Jan 57

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 human Chromosome (Chr) 21q22.1 region contains several genes for cytokines and neurotransmitters and the gene for superoxide dismutase (mutant forms of which can cause familial amyotrophic lateral sclerosis). A region of approximately 5.8 Mb encompassing D21S82 and the glycinamide ribonucleotide transformylase (GART) loci was covered by overlapping YAC clones, which were contiguously ordered by clone walking with sequence-tagged site (STSs). A total of 76 markers, including 29 YAC end-specific STSs, were unambiguously ordered in this 5.8-Mb region, and the average interval between markers was 76 kb. Restriction maps of the YAC clones with rare-cutting enzymes were simultaneously prepared, and the restriction sites were aligned to obtain a consensus restriction map of the proximal region of the 21q22.1 band. The restriction map made from 44 overlapping YACs contains 54 physically assigned STSs. By integrating the consensus map of the adjacent 1.8-Mb region, we obtained a fine physical map spanning 6.5 Mb of human Chr 21q22.1. This map contains 24 precisely positioned end-specific STSs and 12 NotI-linking markers. More than 39 potential CpG islands were identified in this region and were found to be unevenly distributed. This physical map and the YACs should be useful as a reference map and as a resource for further structural analysis of the Giemsa-negative band (R-band) of Chr 21q22.1.
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PMID:A long-range physical map of human chromosome 21q22.1 band from the YAC continuum. 866 3

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

Mutation analysis of the superoxide dismutase gene SOD1 in a familial case of amyotrophic lateral sclerosis revealed a T --> C transition at codon 151 of exon 5. This mutation results in the substitution of an isoleucine for a threonine. It appears to affect formation of dimers of the protein and is the most C-terminal amino acid change in SOD1 described to date.
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PMID:Superoxide dismutase 1: identification of a novel mutation in a case of familial amyotrophic lateral sclerosis. 868 5

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

Oxidative mechanisms of damage have been implicated indirectly in the damage to brain tissue caused acutely by ischemia or chronically by neurodegenerative diseases. A direct link between pathogenesis and antioxidant enzyme systems has come from studies of a genetic form of amyotrophic lateral sclerosis (ALS). ALS causes the degeneration of motor neurons in cortex, brainstem and spinal cord with consequent progressive paralysis and death. The disease occurs in both sporadic and familial forms. Some 20% of kindreds in which ALS is inherited in an autosomal dominant fashion have mutations in the gene (SOD1) encoding Cu, Zn superoxide dismutase (SOD). Several SOD1 mutations have been shown by ourselves and others to cause motor neuron disease when expressed at high levels in transgenic mice, whereas transgenic mice expressing comparable amounts of wild-type human SOD do not show clinical disease. Thus, we have argued that motor neuron disease is caused by gain-of-function mutations in the human SOD1 gene. Our current experiments investigate the link between mutation of SOD1 and oxidative pathways of damage.
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PMID:Pathogenic mechanisms in familial amyotrophic lateral sclerosis due to mutation of Cu, Zn superoxide dismutase. 873 1

A family with autosomal-dominant amyotrophic lateral sclerosis with histopathological confirmation on autopsy was described. A 42-year-old female proband showed the signs and symptoms only in the lower limbs characteristic of lower motor neuron involvement at the onset. ALS had been diagnosed in other five members in three generations of her family. The mean +/- SD age of onset of the disease was 42.5 +/- 9.3 years with a range of 30 to 51 years. The mean +/- SD duration of the disease (n = 5, excluding the proband) was 56 +/- 70 months with a range of 7 to 180 months. Molecular genetic studies showed a T-to-G transversion that results in the substitution of valine for leucine84 in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene on chromosome 21 in a proband. This mutation is identical to that found in the Japanese family with autosomal-dominant ALS characterized by short duration of the disease, within 1.5 years, in all the affected family members. Therefore, the clinical phenotype, especially the duration of the disease seems to be highly variable even in the families with the identical mutation of the Cu/Zn SOD gene.
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PMID:[Familial amyotrophic lateral sclerosis showing variable clinical courses with (Leu84-->Val) mutation of Cu/Zn superoxide dismutase]. 874 55


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