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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recently, point mutations in superoxide dismutase 1 (SOD1) have been shown to lead to a subset of autosomal dominantly inherited familial amyotrophic lateral sclerosis (ALS). These findings have led to the hypothesis that defects in oxygen radical metabolism may be involved in the pathogenesis of ALS. Therefore, we decided to analyze other enzymes involved in oxygen radical metabolism for possible involvement in other forms of ALS. We report here analysis of two genes encoding the molybdenum hydroxylases aldehyde oxidase (AO) and xanthine dehydrogenase/oxidase (XDH) for involvement in ALS. Of particular interest, one gene identified as encoding aldehyde oxidase is shown to map to 2q33, a region recently shown to contain a gene responsible for a familial form of ALS with autosomal recessive inheritance (FALS-AR). The AO gene appears to be located within 280,000 bp of simple sequence repeat marker D2S116, which shows no recombination with the FALS-AR locus. The AO gene is highly expressed in glial cells of human spinal cord. In addition, we mapped a gene for XDH to 2p22, a region previously shown to contain a highly homologous but different form of XDH. Neither of these XDH genes appears to be highly expressed in human spinal cord. This evidence suggests that AO may be a candidate gene for FALS-AR.
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PMID:Analysis of aldehyde oxidase and xanthine dehydrogenase/oxidase as possible candidate genes for autosomal recessive familial amyotrophic lateral sclerosis. 757 Jan 84

We investigated the applications of back propagation artificial neural networks (ANN) for a small dataset analysis in the field of structure-activity relationships. The derivatives of carboquinone were used as an example. It's been found that in this case the use of the same neural network results in unambiguous classification of new molecules. Predictions can be improved with statistical analysis of independent prognosis sets. We suggest that the sign criterion be used as a classification rule. We also compared neural networks with FALS and ALS in leave-one-out prediction. ANN applied to the same dataset has shown the same predictive ability as ALS but poorer than FALS.
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PMID:Applications of neural networks in structure-activity relationships of a small number of molecules. 846 34

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder affecting primarily upper and lower motor neurons. In all cases of ALS, approximately 5-10% of cases are familial (FALS). Missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been demonstrated in some families of FALS since 1993. We have also identified a novel missense mutation (substitution of Thr for Ala4) in exon 1 in a Japanese FALS family, and clarified the pathological findings of a patient in this family were typical of FALS with posterior column involvement. However, the mechanism by which the mutations in SOD1 lead to ALS is unknown. It is now clear that the mutations in SOD1 reduce total SOD activities only by 30-60%, and there is doubt whether a reduction in enzymatic function of this magnitude suffices to cause the neuronal loss. Recently, transgenic mice expressing the mutant SOD1 demonstrate motor neuron degeneration despite an increased level of SOD activity. The process of motor neuron degeneration in FALS might be mediated by some novel functions of the mutant SOD1 protein.
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PMID:[Familial amyotrophic lateral sclerosis and mutations in the Cu/Zn superoxide dismutase gene]. 875 59

Animal models of amyotrophic lateral sclerosis (ALS) provide a unique opportunity to study this incurable and fatal human disease both clinically and pathologically. This is particularly true for certain pathological and therapeutic studies that are impractical or impossible to perform in human patients. Nonetheless, postmortem ALS tissue remains the "gold standard" against which pathologic findings in animal models must be compared. Four natural disease models have been most extensively studied, including three mouse models: motor neuron degeneration (Mnd), progressive motor neuronopathy (pmn), wobbler, and one canine model: hereditary canine spinal muscular atrophy (HCSMA). The wobbler mouse has been the most extensively studied of these models with analyses of clinical, pathological (perikaryon, axon, muscle), and biochemical features. Experimentally induced ALS animal models have allowed controlled testing of various neurotoxic, viral and immune-mediated mechanisms. Molecular techniques have recently generated mouse models in which genes relevant to the human disease or motor neuron biology have been manipulated. The most clinically relevant of these is a transgenic mouse overexpressing the mutated SOD1 gene of FALS patients, which has already provided significant insights into mechanisms of motor neuron degeneration in this disease. Because no single animal model perfectly reflects all the clinical and pathological characteristics of ALS, study of selected features from the most relevant models will contribute to a better understanding of the pathogenesis and/or etiology of this disease.
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PMID:Animal models of ALS. 902 Dec 59

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that primarily affects motor neurons in the spinal cord and brain stem. About 10% of all ALS cases are familial (FALS), inherited in an autosomal dominant manner. One fifth of FALS patients carry mutations in the Cu/Zn superoxide dismutase (SOD1) gene, and several lines of transgenic mice have been engineered to express mutant forms of the SOD1 gene that are linked to FALS. Significantly, many of these transgenic lines of mice develop a motor neuron disease (MND) that resembles human FALS. Oxidative stress induced by human SOD1 mutations is believed to play an important role in the pathogenesis of FALS and the FALS-like MND seen in the mutant SOD1 transgenic mice. For example, two lines of these mice showed prominent degeneration of mitochondria and endoplasmic reticulum in spinal cord neurons. Furthermore, recent studies have shown that neurofilament (NF)-rich spheroids. Lewy body-like NF inclusions, altered ubiquitin immunoreactivity, and Golgi fragmentation occur in the spinal cord motoneurons of these mutant SOD1 transgenic mice. Because these lesions recapitulate hallmark abnormalities of human ALS, mutant SOD1 transgenic mice provide a useful model for studies designed to elucidate the pathogenesis of ALS. Furthermore, transgenic mice that overexpress NF proteins also develop a clinical and pathologic phenotype similar to human MND, and polymorphisms in an NF gene have been linked to patients with ALS. Collectively, these observations implicate NF protein abnormalities in the pathogenesis of this disorder. Accordingly, this review summarizes recent insights into mechanisms of motor neuron degeneration in ALS that have emerged from studies of these new animal models of this neurodegenerative disease.
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PMID:Oxidative stress, mutant SOD1, and neurofilament pathology in transgenic mouse models of human motor neuron disease. 911 7

Amyotrophic lateral sclerosis is sporadic in ninety percent of cases and familial (FALS) in ten percent. Both forms of FALS whether transmitted as an autosomal dominant (DFALS) or as an autosomal recessive (RFALS) trait is genetically heterogeneous. The locus for one form of RFALS maps to chromosome 2q33. Fifteen percent of DFALS families have mutations in the gene for Cu, Zn superoxide dismutase (SOD1) gene which is coded on chromosome 21. These mutations result in decreased SOD1 activity and shortened half-life of the protein in most instances. Transgenic mice overexpressing mutated SOD1 protein develop an ALS-like disease which suggests that the degeneration of motor neurons in DFALS is caused by the gain of a novel toxic function by mutated SOD1 rather than by the decrease of SOD1 activity. Possible mechanisms of the novel neurotoxic function of mutated SOD1 are discussed.
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PMID:Familial amyotrophic lateral sclerosis. 926 31

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 X-ray crystal structure of a human copper/zinc superoxide dismutase mutant (G37R CuZnSOD) found in some patients with the inherited form of Lou Gehrig's disease (FALS) has been determined to 1.9 angstroms resolution. The two SOD subunits have distinct environments in the crystal and are different in structure at their copper binding sites. One subunit (subunit[intact]) shows a four-coordinate ligand geometry of the copper ion, whereas the other subunit (subunit[broken]) shows a three-coordinate geometry of the copper ion. Also, subunit(intact) displays higher atomic displacement parameters for backbone atoms ((B) = 30 +/- 10 angstroms2) than subunit(broken) ((B) = 24 +/- 11 angstroms2). This structure is the first CuZnSOD to show large differences between the two subunits. Factors that may contribute to these differences are discussed and a possible link of a looser structure to FALS is suggested.
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PMID:Subunit asymmetry in the three-dimensional structure of a human CuZnSOD mutant found in familial amyotrophic lateral sclerosis. 954 85

This study examined high affinity Na+-dependent uptake of glutamate in synaptosomal preparations from spinal cord in mice that express a dominant mutation of human copper/zinc superoxide dismutase (SOD1) and represent an animal model of amyotrophic lateral sclerosis (ALS). Their muscle strength was also monitored by a grip traction test throughout their lifespan. The high affinity Na+-dependent uptake of [3H]glutamate was decreased between 120 and 150 days of age. A marked and significant decrease in Vmax (-40.2%; p < 0.001) on whole spinal cord synaptosomes was observed at 150 days, with no change in Km. This significant decrease was reached a week before the animals died (157.2 +/- 2.2 days) and corresponded to a considerable fall in muscle strength (25% loss between 120 and 140 days, p < 0.001). The FALS mouse model therefore reproduces the decrease in glutamate uptake reported in humans suffering from sporadic or familial ALS. These results are discussed in terms of a possible tardive involvement of glutamate uptake deficiency in human ALS.
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PMID:Glutamate uptake is decreased tardively in the spinal cord of FALS mice. 957 63

Reactive oxygen (RO) has been identified as an important effector in ageing and lifespan determination. The specific cell types, however, in which oxidative damage acts to limit lifespan of the whole organism have not been explicitly identified. The association between mutations in the gene encoding the oxygen radical metabolizing enzyme CuZn superoxide dismutase (SOD1) and loss of motorneurons in the brain and spinal cord that occurs in the life-shortening paralytic disease, Familial Amyotrophic Lateral Sclerosis (FALS; ref. 4), suggests that chronic and unrepaired oxidative damage occurring specifically in motor neurons could be a critical causative factor in ageing. To test this hypothesis, we generated transgenic Drosophila which express human SOD1 specifically in adult motorneurons. We show that overexpression of a single gene, SOD1, in a single cell type, the motorneuron, extends normal lifespan by up to 40% and rescues the lifespan of a short-lived Sod null mutant. Elevated resistance to oxidative stress suggests that the lifespan extension observed in these flies is due to enhanced RO metabolism. These results show that SOD activity in motorneurons is an important factor in ageing and lifespan determination in Drosophila.
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PMID:Extension of Drosophila lifespan by overexpression of human SOD1 in motorneurons. 962 Jul 57


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