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)

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

A subset of pedigrees with dominant inheritance of familial amyotrophic lateral sclerosis have mutations in superoxide dismutase 1. Initial studies suggested that disease-linked mutations impaired superoxide dismutase 1 activity, which is consistent with the notion that disease results from increased oxidative injury. However, results of recent cell culture and transgenic studies demonstrate that mutant proteins retaining high levels of superoxide dismutase 1 activity cause motor neuron degeneration; elevating the level of wild-type superoxide dismutase 1 does not cause disease. These findings suggest that the familial amyotrophic lateral sclerosis phenotype may occur through other mechanisms that can now be explored in model systems.
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PMID:Motor neuron disease caused by mutations in superoxide dismutase 1. 758 45

Mutations in the superoxide dismutase 1 (SOD1) gene have been detected in affected members of some families with familial amyotrophic lateral sclerosis. To evaluate the possibility of a shared genetic defect in amyotrophic lateral sclerosis and Parkinson's disease, the SOD1 gene was sequenced in index patients with familial Parkinson's disease from 23 families. No changes were detected.
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PMID:Sequence of the superoxide dismutase 1 (SOD 1) gene in familial Parkinson's disease. 760 18

Mutations in superoxide dismutase 1 (SOD1) have been linked to familial amyotrophic lateral sclerosis, a dominantly inherited motor neuron disorder of midlife. Because SOD1 is a homodimeric enzyme, dimerization of mutant and wild-type SOD1 subunits could dominantly alter the activity, stability, or localization of wild-type SOD1 subunits. To explore these possibilities, we used transient and stable gene transfection to express high levels of either of two mutant human SOD1 subunits in the presence of limited levels of wild-type mouse and/or human SOD1 subunits. Although both mutant subunits displayed diminished half-lives and free radical scavenging activities, their presence caused no change in the half-life or activity of wild-type SOD1 subunits. Our data indicate that mutant subunits do not dominantly affect the function of wild-type SOD1 subunits. These findings, together with observations that many mutant SOD1 subunits retain significant stability and activity, suggest that motor neuron damage in familial amyotrophic lateral sclerosis is caused by the acquisition of injurious properties by mutant SOD1 subunits.
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PMID:Superoxide dismutase 1 subunits with mutations linked to familial amyotrophic lateral sclerosis do not affect wild-type subunit function. 785 9

Mutation in superoxide dismutase 1 (SOD1), a Cu/Zn enzyme that removes oxygen radicals and protects against oxidative injury, has been implicated in some cases of familial amyotrophic lateral sclerosis (FALS). As a first approach to examining the mechanism(s) through which these mutations cause specific degeneration of motor neurons, we have used immunocytochemistry to identify the distribution of SOD1 in populations of cells in the peripheral and central nervous systems. In the spinal cord, intense SOD1 immunoreactivity was present in motor neurons, interneurons, and substantia gelatinosa. In motor neurons, SOD1 immunoreactivity was abundant in perikarya, dendrites, and axons; most of this activity appeared to be free in the cytoplasm, although a portion was associated with membranous vesicles, presumably peroxisomes. Since a variety of central nervous system neurons, including pyramidal cells in cerebral cortex and neurons of the CA3 and CA4 sectors of the hippocampus, showed high immunoreactivity but are unaffected in ALS, the apparent abundance of SOD1 does not predict vulnerability of neurons to mutations in SOD1. Rather, SOD1 accumulates in many neuronal populations but is particularly abundant in motor neurons. Consistent with recent studies of FALS-linked SOD1 mutations in vitro and in transgenic mice, our findings offer further support for the view that the mutations confer a gain of adverse function. In this view, high, rather than limiting, levels of SOD1 may place motor neurons selectively at risk in FALS.
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PMID:Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons. 786 72

Familial amyotrophic lateral sclerosis (FALS) has been linked to mutations in the homodimeric enzyme Cu/Zn superoxide dismutase 1 (SOD1). Assay by transient expression in primate cells of six FALS mutant enzymes revealed a continuum of enzymatic activity bounded by the enzyme carrying the mutation Gly-85-->Arg, which was inactive, and mutant enzyme G37R carrying the Gly-37-->Arg change, which retained full specific activity but displayed a 2-fold reduction in polypeptide stability. The G37R mutant displayed similar properties in transformed lymphocytes from an individual heterozygous for the G37R and wild-type SOD1 genes; heterodimeric enzymes composed of mutant and wild-type subunits were detected, but there was no measurable diminution in the stability and activity of the wild-type subunits. Thus, for mutants such as G37R, either surprisingly modest losses in activity (involving only the mutant subunit) can yield motor neuron death, or alternatively, mutant SOD1 may acquire properties that injure motor neurons by one or more mechanisms unrelated to the metabolism of oxygen radicals.
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PMID:Superoxide dismutase 1 with mutations linked to familial amyotrophic lateral sclerosis possesses significant activity. 805 97

A superoxide dismutase 1 (SOD-1)genetic defect has been identified in familial amyotrophic lateral sclerosis (ALS) and motor neuron degeneration has been described in SOD-1 transgenic mice. Because an excitotoxic mechanism has been implicated in ALS, we undertook studies to provide a description of excitotoxic degeneration of spinal motor neurons for comparison with the degenerative process observed in SOD-1 transgenic mice. Excitotoxin agonists selective for each of the three major types of inotropic glutamate receptors were applied directly onto the lumbar spinal cord of 21-day old rats following posterior laminectomy. N-methyl-D-aspartate (NMDA) preferentially affected dorsal horn neurons, whereas the non-NMDA agonist, kainic acid, preferentially affected motor neurons. Cytopathological changes in motor neurons closely resembled those described in SOD-1 mice. These changes consist of massively swollen dendritic processes in the presence of well-preserved presynaptic axon terminals; cell bodies of motor neurons filled with vacuoles that originate both from endoplasmic reticulum and mitochondria; pleomorphic changes in mitochondria; axons of motor neuron becoming swollen proximally with accumulation of vacuoles, organelles, filaments, and degeneration products in the swollen segment. The observed changes in motor axons resemble changes described in the spinal cord of ALS patients. These findings are consistent with the proposal that motor neuron degeneration in ALS may be mediated by an excitotoxic process involving hyperactivation with non-NMDA glutamate receptors.
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PMID:Motor neuron degeneration induced by excitotoxin agonists has features in common with those seen in the SOD-1 transgenic mouse model of amyotrophic lateral sclerosis. 878 80

We performed a comparative neuropathological study on two siblings with familial amyotrophic lateral sclerosis (FALS). The clinical course of the sister who died at age 46 was 18 months, and that of the brother who died at age 65, 11 years. The neuropathological findings of the female were compatible with FALS with posterior column involvement. Her brother had multisystem degeneration in addition to the motor neuron disturbance; Lewy body-like hyaline inclusions (LBHIs) were present in the affected neurons of the degenerative lesions. Eosinophilic inclusions were seen in many astrocytes of the affected areas of the male FALS patient. Immunohistochemical assays revealed that most astrocytic inclusions reacted with the antibodies against Cu/Zn-superoxide dismutase 1 (SOD1) and ubiquitin; immunoreactivity was essentially the same as that of the neuronal LBHIs. Ultrastructurally the astrocytic inclusions were composed mainly of 15- to 25-nm granule-coated fibrils and granular material, resembling LBHIs of the neurons. Despite the dissimilar neuropathological features, both patients had the same two base pair deletion in exon 5 of the SOD1 gene. These findings suggest that FALS due to an SOD1 gene mutation is potentially a multisystem degenerative disorder, affecting not only neurons, but also astrocytes.
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PMID:Familial amyotrophic lateral sclerosis with a two base pair deletion in superoxide dismutase 1: gene multisystem degeneration with intracytoplasmic hyaline inclusions in astrocytes. 885 6

To examine the mechanism(s) of disease underlying ALS, transgenic mouse models have been constructed that express aberrant neurofilaments or mutations in the abundant, cytoplasmic enzyme superoxide dismutase 1 (SOD1). In addition to progressive weakness arising from selective motor neuron death, mice expressing a modest level of a point mutant in neurofilament subunit NF-L show most of the pathologic hallmarks observed in familial and sporadic ALS, including perikaryal proximal axonal swellings, axonal degeneration, and severe skeletal muscle atrophy. Additional mice expressing familial ALS-linked mutations in the cytoplasmic enzyme SOD1, the only proven cause of ALS and which accounts for approximately 20% of familial disease, have demonstrated that at least one mutation causes disease through acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity. These animals not only provide a detailed look at the pathogenic progression of disease, but also represent a tool for testing hypotheses concerning the specific mechanism(s) of neuronal death and for testing therapeutic strategies.
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PMID:Mechanisms of selective motor neuron death in transgenic mouse models of motor neuron disease. 885 52

The phenotypes of many neurological diseases, including motor neuron disease (amyotrophic lateral sclerosis; ALS) and Alzheimer's disease (AD), are determined by the vulnerabilities of populations of nerve cells and the character/ evolution of cellular abnormalities. Because different cell types respond selectively to individual trophic factors, these factors may be useful in ameliorating pathology in cells that express their cognate receptors. To test therapies for ALS and AD, investigators require model systems. Although there are a variety of models of ALS, two models are particularly attractive: transgenic mice that express human superoxide dismutase 1 (SOD-1) mutations linked to familial ALS develop paralysis associated with a gain of adverse property of the mutant SOD; and axotomy of facial axons in neonatal rats, a manipulation that causes retrograde cell degeneration, which can be ameliorated by several trophic factors.
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PMID:Motor neuron disease and model systems: aetiologies, mechanisms and therapies. 886 25


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