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)

Some cases of autosomal-dominant familial amyotrophic lateral sclerosis (FALS) have been associated with mutations in SOD1, the gene that encodes Cu/Zn superoxide dismutase (Cu/Zn SOD). We determined the concentrations (microgram of Cu/Zn SOD/mg of total protein), specific activities (U/microgram of total protein), and apparent turnover numbers (U/mumol of Cu/Zn SOD) of Cu/Zn SOD in erythrocyte lysates from patients with known SOD1 mutations. We also measured the concentrations and activities of Cu/Zn SOD in FALS patients with no identifiable SOD1 mutations, sporadic ALS (SALS) patients, and patients with other neurologic disorders. The concentration and specific activity of Cu/Zn SOD were decreased in all patients with SOD1 mutations, with mean reductions of 51 and 46%, respectively, relative to controls. In contrast, the apparent turnover number of the enzyme was not altered in these patients. For the six mutations studied, there was no correlation between enzyme concentration or specific activity and disease severity, expressed as either duration of disease or age of onset. No significant alterations in the concentration, specific activity, or apparent turnover number of Cu/Zn SOD were detected in the FALS patients with no identifiable SOD1 mutations, SALS patients, or patients with other neurologic disorders. That Cu/Zn SOD concentration and specific activity are equivalently reduced in erythrocytes from patients with SOD1 mutations suggests that mutant Cu/Zn SOD is unstable in these cells. That concentration and specific activity do not correlate with disease severity suggests that an altered, novel function of the enzyme, rather than reduction of its dismutase activity, may be responsible for the pathogenesis of FALS.
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PMID:Superoxide dismutase concentration and activity in familial amyotrophic lateral sclerosis. 772 23

Two different lines of mice, G1 and G20, carrying a transgene for a mutant form of Cu,Zn SOD, found in a family with familial amyotrophic lateral sclerosis (FALS), develop clinical and pathological changes which are, in their late stages, strikingly similar to those in human disease. We have analyzed the distribution and characteristics of lesions in the central and peripheral nervous systems of such mice. The most affected structure was the spinal cord, followed by the medulla, pons and midbrain. The early stages of the disease were characterized by vascular degeneration of anterior horn neurons and their processes, while, in the late stages, the main changes consisted of neuronal loss and atrophy of the anterior horns and the deposition in these areas of multiple filamentous inclusions resembling Lewy bodies. In the late stages of the disease, the white matter of the spinal cord was also involved, particularly in the anterior and lateral columns. Posterior columns were also involved, but to a much lesser degree. The brainstem structures also showed vacuolar degeneration of several motor nuclei and of several groups neurons in the reticular formation. Anterior roots and peripheral nerves showed the classical features of Wallerian degeneration. The dorsal root ganglia, with rare exceptions, were unremarkable. The posterior roots showed mild changes in the most severely affected mice. Changes in these two affected lines were compared to changes in mice overexpressing wild type, rather than mutant human Cu,Zn SOD. These mice never developed clinical disease, although, pathologically, they developed very mild vacuolar changes in the anterior horns of the spinal cord and in motor axons. This study shows that although simple overexpression of SOD may be injurious to motor neurons, albeit very mildly, the mutant form is necessary to produce both clinical disease and severe pathological changes which, in the chronic stage of the disease, have striking similarities to human familial ALS. A dominant gain of function, therefore, is the most likely pathogenesis of tissue injury induced by mutations in Cu,Zn SOD.
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PMID:Neuropathological changes in two lines of mice carrying a transgene for mutant human Cu,Zn SOD, and in mice overexpressing wild type human SOD: a model of familial amyotrophic lateral sclerosis (FALS). 779 76

Amyotrophic lateral sclerosis (ALS) is a progressive, adult-onset, neurodegenerative disorder characterized by the death of large motor neurons from the cerebral cortex, brainstem, and spinal cord. The etiology of ALS remains unknown; however, approximately 10% of the cases are familial in nature. In the majority of these families, the mode of transmission is autosomal dominant. Recently, linkage of an autosomal dominant familial ALS (FALS) gene to the locus ALS1 on chromosome 21q was established. In addition, evidence was provided for genetic heterogeneity, with approximately 55% of families most likely linked to chromosome 21. The development of a number of highly informative simple sequence repeat polymorphisms in the region of linkage-21q21 through 21q22.1-has permitted us to confirm both the assignment of ALS1 to 21q and the genetic heterogeneity of FALS. In addition, we have been able to refine the mapping of ALS1, based on recombination events in two of the linked families. Flanking markers for the FALS gene are D21S213 on the centromeric side and D21S219 on the telomeric side. The candidate region is approximately 4 Mb and contains the genes copper/zinc superoxide dismutase (CuZnSOD); the fourth member of the class II cytokine receptor family (CRF2-4); and the interferon-alpha receptor (IFNAR).
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PMID:Identification of flanking markers for the familial amyotrophic lateral sclerosis gene ALS1 on chromosome 21. 780 55

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurological disorder that results in relentless damage to the motor neuron system. Although about 5-10% of cases are familial, the pathophysiologic process of ALS remains unknown. We identified a novel point mutation A to G in exon 2 of the Cu/Zn SOD gene, resulting in an amino acid substitution of histidine46 by arginine (H46R), in two Japanese familial ALS (FALS) families. The segregations of the mutation were evident. The enzymatic activities of Cu/Zn SOD of peripheral red blood cell lysate were reduced to about 80% in the affected members, compared with other non-affected family members. The patients in these families are clinically characterized by relative late onset, initial involvement in lower extremities, relative rare impairment of bulbar muscles and much slow progression of muscular weakness and atrophy, compared with other Japanese FALS cases who have no mutation in the Cu/Zn SOD gene. These findings suggest that the H46R mutation in Cu/Zn SOD gene is highly related to this unique subtype of FALS.
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PMID:Familial amyotrophic lateral sclerosis (ALS) in Japan associated with H46R mutation in Cu/Zn superoxide dismutase gene: a possible new subtype of familial ALS. 783 51

Amyotrophic lateral sclerosis is a progressive neurodegenerative disorder primarily involving motoneurons. A subset of individuals with familial autosomal dominant forms of the disease have mutations of the copper/zinc superoxide dismutase (Cu/Zn SOD, SOD-1) gene, which encodes a ubiquitously expressed enzyme that plays a key role in oxygen free radical scavenging. This observation suggests that altered or reduced SOD-1 activity may play a role in the neurodegenerative process. To explore this possibility further, we have introduced a mutation into the mouse SOD-1 gene that corresponds to one of the changes found in the human gene in familial amyotrophic lateral sclerosis. Integration and expression of this mouse gene in transgenic mice was identified by the presence of a unique restriction enzyme site in the transgene coding sequence generated by introduction of the mutation. We report here that high expression of this altered gene in the central nervous systems of transgenic mice is associated with an age-related rapidly progressive decline of motor function accompanied by degenerative changes of motoneurons within the spinal cord, brain stem, and neocortex. These findings indicate a causative relationship between altered SOD activity and motoneuron degeneration. Moreover, biochemical studies indicate normal levels of total SOD activity in transgenic mouse tissues, results that indicate that the neurodegenerative disorder does not result from a diminution of activity and, as such, represents a dominant "gain of function" mutation.
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PMID:Transgenic mice expressing an altered murine superoxide dismutase gene provide an animal model of amyotrophic lateral sclerosis. 784 37

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder affecting motor neurons. Although most cases of ALS are sporadic, approximately 10% are inherited as an autosomal dominant trait. Mutations in the Cu/Zn superoxide dismutase gene (SOD 1) are responsible for a fraction of familial ALS (FALS). Screening our FALS kindreds by SSCP, we have identified mutations in 15 families, of which 9 have not been previously reported. Two of the new mutations alter amino acids that have never been implicated in FALS. One of them affects a highly conserved amino acid involved in dimer contact, and the other one affects the active-site loop of the enzyme. These two mutations reduce significantly SOD 1 enzyme activity in lymphoblasts. Our results suggest that SOD 1 mutations are responsible for > or = 13% of FALS cases.
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PMID:Identification of new mutations in the Cu/Zn superoxide dismutase gene of patients with familial amyotrophic lateral sclerosis. 788 12

Mutations in the gene for Cu/Zn superoxide dismutase (SOD1) have been detected in some families with an autosomal dominant form of amyotrophic lateral sclerosis; these mutations appear to reduce the activity of this enzyme. To determine whether decreased SOD activity could contribute to motor neuron loss, SOD1 was inhibited chronically with either antisense oligodeoxynucleotides or diethyldithiocarbamate in spinal cord organotypic cultures. Chronic inhibition of SOD resulted in the apoptotic degeneration of spinal neurons, including motor neurons, over several weeks. Motor neuron loss was markedly potentiated by the inhibition of glutamate transport. In this paradigm, motor neuron toxicity could be entirely prevented by the antioxidant N-acetylcysteine and, to a lesser extent, by the non-N-methyl-D-aspartate glutamate receptor antagonist 1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-5H-2,3-benzodiazepine hydrochloride. These data support the hypothesis that the loss of motor neurons in familial amyotrophic lateral sclerosis could be due to a reduction in SOD1 activity, possibly potentiated by inefficient glutamate transport.
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PMID:Chronic inhibition of superoxide dismutase produces apoptotic death of spinal neurons. 791 Apr 2

Mutations in the Cu, Zn superoxide dismutase (SOD1) gene have been reported in some pedigrees with Familial Amyotrophic Lateral Sclerosis (FALS). We have investigated the functional and structural effects of a Gly-->Ser mutation at codon 41 of SOD1 in a pedigree with FALS and the topography of SOD1 expression in the mammalian CNS. These analyses show that the 41Gly-->Ser mutation causes a 27% reduction in Cu, Zn SOD activity. SOD1 is transcribed at high levels in rat motoneurons and four other types of neurons homologous to upper motoneurons that degenerate in human ALS. However, SOD1 is transcribed at lower levels in other types of neurons, such as cerebellar Purkinje cells, which are not usually involved significantly in human ALS. On the other hand, immunocytochemical studies indicate that most types of rat neurons contain similar levels of Cu, Zn SOD immunoreactive protein. Nevertheless, these results suggest that the essential feature causing this subtype of ALS is either a reduction in Cu, Zn SOD activity in cell types that presumably critically require Cu, Zn SOD for protection against oxidative damage or the fact that the mutation in SOD1 associated with FALS results in a novel gain of function that is particularly deleterious to those cell types expressing SOD1 at high levels.
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PMID:Analysis of the functional effects of a mutation in SOD1 associated with familial amyotrophic lateral sclerosis. 791 2

Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.
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PMID:Motor neurone disease. 792 18

Sequences encoding three copper-zinc superoxide dismutase (CuZnSOD) mutant proteins analogous to those coded for in familial amyotrophic lateral sclerosis (fALS) were constructed in the Saccharomyces cerevisiae CuZnSOD gene and expressed in yeast lacking CuZnSOD (sod1-). Gly85-->Arg CuZnSOD failed to rescue the oxygen-sensitive phenotype of sod1- yeast, but Gly93-->Ala CuZnSOD and Lys100-->Gly CuZnSOD were apparently fully functional in vivo. The Gly85-->Arg mutant protein was purified and its metal-binding properties and SOD activity were found to be significantly altered relative to wild type. The Gly93-->Ala CuZnSOD was likewise purified but, in contrast, demonstrated metal-binding comparable to wild type and activity 80% that of wild type. These results suggest that SOD activity of human fALS mutant CuZnSODs may vary considerably in vivo, with at least some of them retaining a considerable amount of activity. Alternative theories to increased free-radical damage should be considered in attempting to explain fALS.
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PMID:Characterization of three yeast copper-zinc superoxide dismutase mutants analogous to those coded for in familial amyotrophic lateral sclerosis. 793 15


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