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)

Aging is a major risk factor for several common neurodegenerative diseases, including Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Huntington's disease (HD). Recent studies have implicated mitochondrial dysfunction and oxidative stress in the aging process and also in the pathogenesis of neurodegenerative diseases. In brain and other tissues, aging is associated with progressive impairment of mitochondrial function and increased oxidative damage. In PD, several studies have demonstrated decreased complex I activity, increased oxidative damage, and altered activities of antioxidant defense systems. Some cases of familial ALS are associated with mutations in the gene for Cu, Zn superoxide dismutase (Cu, Zn SOD) and decreased Cu, Zn SOD activity, while in sporadic ALS oxidative damage may be increased. Defects in energy metabolism and increased cortical lactate levels have been detected in HD patients. Studies of AD patients have identified decreased complex IV activity, and some patients with AD and PD have mitochondrial DNA mutations. The age-related onset and progressive course of these neurodegenerative diseases may be due to a cycling process between impaired energy metabolism and oxidative stress.
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PMID:Bioenergetic and oxidative stress in neurodegenerative diseases. 747 93

Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.
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PMID:A radical hypothesis for neurodegeneration. 752 Feb

1. Clonal cell lines, primary cultured neurones and transgenic animals expressing mutant genes linked to familial forms of neurodegenerative diseases provide models in which to examine the interaction between expression of a predisposing gene and exposure to neurotoxic chemicals. Methods of establishing these models are reviewed. 2. Mutations in the gene encoding Cu/Zn-superoxide dismutase (SOD-1) have been identified in cases of familial amyotrophic lateral sclerosis linked to chromosome 21. We report that in clonal lines of PC12 cells, the cytotoxicity of a glutathione-depleting epoxide, styrene oxide, varied with SOD activity in a manner similar to that previously demonstrated for redox cycling chemicals. These preliminary data suggest that either low or high SOD-1 activities may be associated with greater toxicity of a variety of neurotoxic chemicals and their metabolites.
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PMID:Use of tissue culture models to study environmental-genetic interactions relevant to neurodegenerative diseases. 755 32

Point mutations in the gene encoding Cu,Zn superoxide dismutase (SOD1) are associated with autosomal dominant familial amyotrophic lateral sclerosis (FALS). We have measured Cu,Zn SOD activity in lymphoblastoid cells from affected and at risk FALS patients carrying mutations in the SOD1 gene, FALS patients without mutations in the SOD1 gene, individuals affected by the sporadic form of the disease (SALS), normal controls and individuals with other neurological abnormalities. The results show a significant decrease in Cu,Zn SOD activity in affected and at risk FALS individuals as compared to FALS patients without mutations, SALS individuals, normal and neurological controls. It is concluded that decreased SOD activity may contribute, together with other as yet unknown factors, to motor neurone demise.
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PMID:Superoxide dismutase activity in lymphoblastoid cells from motor neurone disease/amyotrophic lateral sclerosis (MND/ALS) patients. 759 31

We studied the gene for Cu,Zn SOD in 15 German patients with familial ALS and did not find any mutation. Activity of the enzyme and its expression at the protein level was also normal in each patient and in 18 patients suffering from the sporadic form of ALS.
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PMID:Cu,Zn SOD in German families with ALS. 759 32

Familial amyotrophic lateral sclerosis is a degenerative motor neuron disease associated in some cases with the presence of a mutant form of Cu/Zn superoxide dismutase. We have studied the stability of the gly100-->glu mutant in extracts of red cells obtained from members of a family with a history of the disease. Extracts containing the mutant had an average 68% of normal superoxide dismutase activity. On heating at 65 degrees C, these extracts lost activity at twice the rate of extracts containing only the normal enzyme. Decreased heat stability was also evident on native polyacrylamide gel electrophoresis with activity staining. This showed selective loss of first the mutant homodimer and then the heterodimer of the enzyme. Decreased stability intracellularly could be a factor in motor neuron degeneration.
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PMID:Decreased thermal stability of red blood cell glu100-->gly superoxide dismutase from a family with amyotrophic lateral sclerosis. 763 96

Recent reports have shown heterozygosity for some twenty different mutations in the CuZn-superoxide dismutase (CuZn-SOD) gene in familial amyotrophic lateral sclerosis (FALS), and analysed samples from patients have shown decreased enzymic activity. Here we report homozygosity for an exon 4 mutation, Asp90Ala in fourteen patients among four unrelated ALS families and four apparently sporadic ALS patients from Sweden and Finland. The erythrocyte CuZn-SOD activity is essentially normal. Our findings suggest that this CuZn-SOD mutation causes ALS by a gain of function rather than by loss, and that the Asp90Ala mutation is less detrimental than previously reported mutations.
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PMID:Amyotrophic lateral sclerosis associated with homozygosity for an Asp90Ala mutation in CuZn-superoxide dismutase. 764 93

Neuronal injury resulting from acute brain insults and some neurodegenerative diseases implicates N-methyl-D-aspartate (NMDA) glutamate receptors. The fact that antioxidants reduce some types of brain damage suggests that oxygen radicals may have a role. It has been shown that mutations in Cu/Zn-superoxide dismutase (SOD), an enzyme catalysing superoxide (O2.-) detoxification in the cell, are linked to a familial form of amyotrophic lateral sclerosis (ALS). Here we report that O2.- is produced upon NMDA receptor stimulation in cultured cerebellar granule cells. Electron paramagnetic resonance was used to assess O2.- production that was due in part to the release of arachidonic acid. Activation of kainic acid receptors, or voltage-sensitive Ca2+ channels, did not produce detectable O2.-. We also find that the nitrone DMPO (5,5-dimethyl pyrroline 1-oxide), used as a spin trap, is more efficient than the nitric oxide synthase inhibitor, L-NG-nitro-arginine, in reducing NMDA-induced neuronal death in these cultures.
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PMID:NMDA-dependent superoxide production and neurotoxicity. 768 49

Amyotrophic lateral sclerosis (ALS) is a degenerative disorder of motor neurons in the central nervous system (CNS). Mutation of the Cu/Zn-superoxide dismutase (SOD) gene on chromosome 21 has been found in some families with autosomal dominant familial ALS (FALS). We sought to determine whether there may be differences in the distribution and activity of SOD in the CNS of patients with sporadic ALS, and of control patients without neurological disorders. The frontal cortex, cerebellum, and spinal cord were obtained at autopsy on 5 patients with ALS and from 10 controls. Immunohistochemically, in the controls, the cytosols of the large pyramidal neurons of the cerebral cortex, anterior and posterior horn cells, and neurons of the nucleus thoracicus of spinal cord were stained homogeneously with anti-human Cu/Zn-SOD antibody, and in a granular manner with anti-human Mn-SOD antibody. Pia mater and epithelial cells of choroid plexus also stained well. Conversely, in the CNS of the ALS patients, most neurons were stained faintly, or not at all with both anti-Cu/Zn- and Mn-SOD antibodies, whereas the pia mater and the epithelial cells of choroid plexus stained intensely. There was no difference in total SOD activity in the entire CNS between ALS patients and controls, as determined by enzyme assay. Results suggest that, in cases of sporadic ALS, the activities of Cu/Zn- and Mn-SOD are decreased and superoxide produced within the neurons accumulates because of an insufficient elimination, leading to the development or acceleration of cell damage, ultimately producing neuronal degeneration and necrosis.
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PMID:Decrease in Cu/Zn- and Mn-superoxide dismutase activities in brain and spinal cord of patients with amyotrophic lateral sclerosis. 769 93

Familial amyotrophic lateral sclerosis (FALS) is associated with mutations in SOD1, the gene encoding copper/zinc superoxide dismutase (CuZnSOD). However, the mechanism by which these mutations lead to amyotrophic lateral sclerosis is unknown. We report that FALS mutant SODs expressed in yeast lacking CuZnSOD are enzymatically active and restore the yeast to the wild-type phenotype. In mammalian neural cells, the overexpression of wild-type SOD1 inhibits apoptosis induced by serum and growth factor withdrawal or calcium ionophore. In contrast, FALS-associated SOD1 mutants promote, rather than inhibit, neural apoptosis, in a dominant fashion, despite the fact that these mutants retain enzymatic SOD activity both in yeast and in mammalian neural cells. The results dissociate the SOD activity of FALS-associated mutants from the induction of neural cell death, suggesting that FALS associated with mutations in SOD1 may not be simply the result of a decrease in the enzymatic function of CuZnSOD. Furthermore, the results provide an in vitro model that may help to define the mechanism by which FALS-associated SOD1 mutations lead to neural cell death.
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PMID:Mutations associated with amyotrophic lateral sclerosis convert superoxide dismutase from an antiapoptotic gene to a proapoptotic gene: studies in yeast and neural cells. 770 68


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