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)

Recent discoveries on linkage of the gene mutation of an enzyme, copper/zinc superoxide dismutase 1 (SOD-1), to familial amyotrophic lateral sclerosis (ALS) (which constitutes about 1% of all ALS cases) and several transgenic mouse models of ALS have shed light on potential pathogenetic processes involved in this disease. Any speculation as to the pathogenesis of ALS must reflect the unique neurobiology of motor neurons. The most distinctive aspects of motor neurons are their asymmetry, large size, and enormously elongated and thick axons. These characteristics also contribute to their vulnerability to ALS. The determinants of these unique properties are the intermediate cytoskeletal filaments, and the neurofilaments of motor neurons. This characteristic is not exclusive to motor neurons and is shared with other neurons with long axons, including some sensory neurons that are also involved in ALS. The histopathology of the early stages of ALS overwhelmingly suggests that accumulation and aggregation of neurofilaments within motor neurons is intimately related to the morphogenesis of the unique cytoplasmic inclusions, and plays a central role in the pathogenesis of the disease. Understanding of the causal relationship and the morphogenesis of inclusion bodies is critical in any attempt to reverse this complex disease process, which potentially involves the neurotoxic effects of free radicals (nitric oxide, superoxide, hydrogen peroxide, and peroxynitrite, etc) on neurofilaments. By emphasizing the unique make-up of motor neurons, this review intends to reevaluate and reinterpret the basic neuropathology of ALS in the light of recent molecular genetic-data.
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PMID:Neuropathology of amyotrophic lateral sclerosis: new perspectives on an old disease. 926 52

Rosen et al. have reported point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD 1) gene in some families with familial amyotrophic lateral sclerosis (ALS). To determine whether decreased SOD activity could contribute to neuronal damage, rat embryo ventral spinal cord neurons were incubated with diethyldithiocarbamate (DDC), an inhibitor of SOD. There was a marked increase in neuronal damage in cultures exposed to DDC and this phenomenon was dose-related. In this paradigm, these deteriorative changes were prevented by bromocriptine. DDC-treated ventral spinal cord neurons provide an in vitro model of free radical neurotoxicity secondary to decreased SOD activity. Simultaneous treatment with bromocriptine and DDC reduced neurotoxicity, indicating that bromocriptine has a neuroprotective effect against free radicals.
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PMID:Bromocriptine prevents neuron damage following inhibition of superoxide dismutase in cultured ventral spinal cord neurons. 926 19

Copper is distributed to distinct localizations in the cell through diverse pathways. We demonstrate here that the delivery of copper to copper/zinc superoxide dismutase (SOD1) is mediated through a soluble factor identified as Saccharomyces cerevisiae LYS7 and human CCS (copper chaperone for SOD). This factor is specific for SOD1 and does not deliver copper to proteins in the mitochondria, nucleus, or secretory pathway. Yeast cells containing a lys7Delta null mutation have normal levels of SOD1 protein, but fail to incorporate copper into SOD1, which is therefore devoid of superoxide scavenging activity. LYS7 and CCS specifically restore the biosynthesis of holoSOD1 in vivo. Elucidation of the CCS copper delivery pathway may permit development of novel therapeutic approaches to human diseases that involve SOD1, including amyotrophic lateral sclerosis.
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PMID:The copper chaperone for superoxide dismutase. 929 78

Mutations in copper/zinc superoxide dismutase (SOD1) cause a subset of cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS). Transgenic mice that express these point mutations develop progressive paralysis and motor neuron loss thought to be caused by a gain-of-function of the enzyme. The gain-of-function may be an enhanced ability of the mutant SOD1 to generate .OH radicals or to facilitate peroxynitrite-mediated nitration of proteins. We found significant increases in concentrations of 3-nitrotyrosine, a marker of peroxynitrite-mediated nitration, in upper and lower spinal cord and in cerebral cortex of transgenic mice with the FALS-associated G93A mutation. Malondialdehyde, a marker of lipid peroxidation, was increased in cerebral cortex. 3-Nitrotyrosine-, heme oxygenase-1-, and malondialdehyde-modified protein immunoreactivities were increased throughout SOD1 transgenic mice spinal cord but particularly within motor neurons. These results suggest that the gain-of-function of at least one mutant SOD1 associated with FALS involves increased protein nitration and oxidative damage, which may play a role in neuronal degeneration.
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PMID:Increased 3-nitrotyrosine and oxidative damage in mice with a human copper/zinc superoxide dismutase mutation. 930 54

Although a consensus that Alzheimer's disease (AD) is a single disease has not been reached yet, the involvement of the amyloid precursor protein (APP) and betaA4 (A beta) in the pathologic changes advances our understanding of the underlying molecular alterations. Increasing evidence implicates oxidative stress in the neurodegenerative process of AD. This hypothesis is based on the toxicity of betaA4 in cell cultures, and the findings that aggregation of betaA4 can be induced by metal-catalyzed oxidation and that free oxygen radicals may be involved in APP metabolism. Another neurological disorder, familial amyotrophic lateral sclerosis (FALS), supports our view that AD and FALS may be linked through a common mechanism. In FALS, SOD-Cu(I) complexes are affected by hydrogen peroxide and free radicals are produced. In AD, the reduction of Cu(II) to Cu(I) by APP involves an electron-transfer reaction and could also lead to a production of hydroxyl radicals. Thus, copper-mediated toxicity of APP-Cu(II)/(I) complexes may contribute to neurodegeneration in AD.
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PMID:Reactive oxygen species and Alzheimer's disease. 933 68

Some cases of autosomal dominant familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1), suggesting that oxidative damage may play a role in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined markers of oxidative damage to protein, lipids, and DNA in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Protein carbonyl and nuclear DNA 8-hydroxy-2'-deoxyguanosine (OH8dG) levels were increased in SALS motor cortex but not in FALS patients. Malondialdehyde levels showed no significant changes. Immunohistochemical studies showed increased neuronal staining for hemeoxygenase-1, malondialdehyde-modified protein, and OH8dG in both SALS and FALS spinal cord. These studies therefore provide further evidence that oxidative damage may play a role in the pathogenesis of neuronal degeneration in both SALS and FALS.
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PMID:Evidence of increased oxidative damage in both sporadic and familial amyotrophic lateral sclerosis. 934 52

Amyotrophic lateral sclerosis (ALS) is a progressive paralytic disorder resulting from the degeneration of motor neurons in the brain and spinal cord and leading to death within 5 years of symptom onset. The great majority of ALS cases are sporadic, with the familial form (FALS) representing fewer than 10% of all cases. Mutations in the copper/zinc superoxide dismutase 1 (SOD-1) gene have previously been identified as the underlying cause of approximately 20% of FALS cases. As the familial and sporadic forms of the disease are clinically similar, we have sought to determine whether such mutations in SOD-1 underlie any sporadic ALS cases. We have screened 155 sporadic cases by single-strand conformation polymorphism and have identified 4 sporadic cases that possess point mutations in exon 4 of the SOD-1 gene. Two of these mutations are identical to those previously reported in FALS cases. One mutation is novel, resulting in a frameshift at Val118 due to the replacement of G (first base in the last codon of exon 4) by AAAAC. This mutation results in a truncated SOD-1 protein due to the introduction of a stop codon three residues into exon 5.
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PMID:Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis: analysis of 155 cases and identification of a novel insertion mutation. 939 81

The discovery of mutations in the human SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,Zn SOD) in patients with familial amyotrophic lateral sclerosis (ALS) has made possible the development of etiological models of the disease. Expression of mutant SOD1 genes in transgenic mice causes a progressive paralytic disease whose general features resemble ALS in humans. We have used the transgenic model to explore etiological mechanisms and to screen potential therapeutics. Our results and those of others show that familial ALS mutations cause a gain-of-function in Cu,Zn SOD that enhances the generation of damaging oxygen radicals. This may render motor neurons sensitive to the excitotoxic effects of ambient glutamate, as a putative glutamatergic inhibitor such as riluzole has therapeutic efficacy both in the transgenic model and in human ALS. This finding highlights the utility of the SOD1-G93A transgenic mouse model for preclinical drug studies in ALS.
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PMID:The use of transgenic mouse models of amyotrophic lateral sclerosis in preclinical drug studies. 941 57

The recognition of mutations in the copper/zinc superoxide dismutase (SOD1) gene in familial amyotrophic lateral sclerosis (FALS) has been a landmark in ALS research. We report a clinicopathological study of a female patient with FALS showing a two base pair deletion in exon 5 of the SOD1 gene. Her clinical course was rapid and she died 2 years after the onset. The SOD1 activity was down to 30% of the normal level. Western blot analysis did not reveal the mutant protein which was expected to be approximately 2.4 kDa smaller than normal SOD1 protein in molecular mass. In contrast to the neuropathological findings of the previously reported cases showing the same mutation, our case was characterized by sparing of the dorsal column and the presence of only a modest number of intracytoplasmic eosinophilic inclusions showing weak or partial immunoreaction for neurofilament and negative reaction for SOD1. Thus, the same mutation in the SOD1 gene does not necessarily induce consistent pathological changes in the central nervous system.
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PMID:A clinicopathological study of a patient with familial amyotrophic lateral sclerosis associated with a two base pair deletion in the copper/zinc superoxide dismutase (SOD1) gene. 944 65

Mutations of the SOD1 gene, which encodes the enzyme copper/zinc superoxide dismutase, are associated with familial amyotrophic lateral sclerosis (ALS). SOD1 consists of five exons, and over 50 different mutations have been described involving exons 1,2,4 and 5. The absence of mutations in exon 3 has been attributed to a critical function of this exon, its integrity being necessary for the toxic effect of mutant SOD1, and it has been suggested that such mutations may be lethal rather than leading to adult onset disease. We identified the heterozygote mutation Gly72Ser (exon 3) in a family with two individuals affected by ALS. SOD enzyme activity was reduced by 45% when measured in erythrocytes indicating reduced enzyme activity, or reduced stability of the mutant protein. These findings indicate that exon 3 is not a privileged region from mutation; that all five exons should be investigated when seeking SOD1 mutations in human disease; and may help in a better understanding of the pathogenicity of these mutations in ALS.
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PMID:Familial ALS is associated with mutations in all exons of SOD1: a novel mutation in exon 3 (Gly72Ser). 945 77


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