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)

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

Therapeutic trials for amyotrophic lateral sclerosis have attracted much attention, but no drug tested has been effective yet. Three major theories of pathogenesis form the basis for these trials: autoimmunity, chronic excitotoxic stimulation due to accumulation of glutamate, and, in the familial form, peroxidation due to subnormal activity of superoxide dismutase. In striking contrast to the negative results of all of the other drug trials, riluzole (a glutamate antagonist) was said to benefit patients with bulbar onset but not those with spinal onset. Problems with the original trial may be clarified by other studies now in progress. The most optimistic news is the response to therapy of multifocal motor neuropathy, a disorder that clinically resembles motor neuron disease. This year, three groups reported benefit from intravenous immunoglobulin therapy.
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PMID:Amyotrophic lateral sclerosis. 795 38

The spinal muscular atrophies (SMAs) are defined as a group of inherited disorders sharing the common pathological feature of degeneration of the anterior horn cells of the spinal cord and, in some cases, additionally of the bulbar motor nuclei. They are classified according to clinical features, including severity and distribution of muscle weakness and on their modes of inheritance. The SMAs are not uncommon: SMA type I (severe, acute infantile SMA) alone has a gene frequency in the UK estimated at 0.006. Together they represent a significant source of morbidity and mortality. Over the past 3 years, two major advances have been made towards understanding the molecular basis of these clinically heterogeneous disorders. First, in 1990, it was reported that all three forms of childhood-onset proximal SMA were linked to probes mapping to the proximal long arm of chromosome 5. Significant progress has been made towards isolating the gene or genes responsible, and a protocol for prenatal disease prediction in families with a previously severely affected child has been established. Second, in 1991, the molecular defect in adult-onset X-linked spinal and bulbar muscular atrophy was defined as an expansion of a (CAG)n trinucleotide repeat which encodes a string of glutamine residues in the first exon of the androgen receptor. Little progress has been made in elucidating the molecular pathology of the other SMAs. None of them has been linked to chromosome 5q markers, or indeed to markers elsewhere; the conditions are rare and pedigrees generally small. When the gene (or genes) on proximal 5q underlying SMA types I, II and III is cloned, mutations in this can then be sought in the other SMAs. The product of the chromosome 5q gene presumably plays a crucial role in maintaining the integrity of motor neurones, so determination of its structure and function may well have consequences far beyond those pertaining to the inherited SMAs. The identification of pathogenic mutations in the SOD-1 gene in familial amyotrophic lateral sclerosis is of great interest, although it is not clear that similar mechanisms contribute to the more common sporadic form of the disease.
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PMID:Disorders of the motor neurone. 795 56

Several missense mutations within exons 1, 2, 4 and 5 of the gene for Cu/Zn-binding superoxide dismutase (SOD1) have been discovered to be involved in the development of chromosome 21q-linked familial amyotrophic lateral sclerosis (FALS). We describe here an autopsied patient with FALS, in whom we have recently identified a novel missense mutation in exon 1 of the SOD1 gene. The neuropathological findings were compatible with those described previously in patients with FALS with posterior column involvement. This suggests that mutations of the SOD1 gene may be responsible for this form of FALS.
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PMID:Familial amyotrophic lateral sclerosis with a mutation in the Cu/Zn superoxide dismutase gene. 798

Transgenic mice expressing mutant Cu,Zn superoxide dismutase (SOD), containing a substitution of glycine at position 93 by alanine, develop disease prevalently affecting motor neurons. Light microscopical and ultrastructural studies reveal that the earliest pathological features are microvesiculation of large neurons of the anterior horns of the spinal cord. These vacuoles originate from dilation of rough endoplasmic reticulum and from degenerating mitochondria. At the end stage of the disease, the microvesicular pattern gives way to atrophic anterior horns showing severe neuronal depletion and hyaline, filamentous inclusions in some of the surviving neurons. Posterior horn neurons and dorsal root ganglia are not affected. With disease progression, moderate degeneration of anterior and lateral columns, severe degeneration of anterior roots, and mild degeneration in posterior columns and roots become apparent. This study shows that a mutation in SOD, known to occur in a percentage of familial amyotrophic lateral sclerosis patients, may affect only selective neuronal populations, although SOD is a ubiquitous enzyme.
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PMID:Development of central nervous system pathology in a murine transgenic model of human amyotrophic lateral sclerosis. 799 31

Down's Syndrome (DS), the phenotypic expression of human trisomy 21, is presumed to result from overexpression of certain genes residing on chromosome 21 at the segment 21q22-the Down locus. The "housekeeping" enzyme CuZn-superoxide dismutase (CuZnSOD) is encoded by a gene from that region and its activity is elevated in DS patients. Moreover, the recent discovery that familial ALS is associated with mutations in the gene encoding CuZnSOD, focused attention on the entanglement of oxygen-free radicals in cell death and neuronal disorders. To investigate the involvement of CuZnSOD gene dosage in the etiology of the syndrome we have developed both cellular and animal models which enabled us to investigate the physiological consequences resulting from overexpression of the CuZnSOD gene. Rat PC12 cells expressing elevated levels of transfected human CuZnSOD gene were generated. These transformants (designated PC12-hSOD) closely resembled the parental cells in their morphology, growth rate, and response to nerve growth factor, but showed impaired neurotransmitter uptake. The lesion was localized to the chromaffin granule transport mechanism. These results show that elevation of CuZnSOD activity interferes with the transport of biogenic amines into chromaffin granules. Since neurotransmitter uptake plays an important role in many processes of the central nervous system, CuZnSOD gene-dosage may contribute to the neurobiological abnormalities of Down's Syndrome. As an approach to the development of an animal model for Down's Syndrome, several strains of transgenic mice which carry the human CuZnSOD gene have been prepared. These animals express the transgene as an active enzyme with increased activity from 1.6 to 6.0-fold in the brains of four transgenic strains and to an equal or lesser extent in several other tissues. To investigate the contribution of CuZnSOD gene dosage in the neuropathological symptoms of Down's Syndrome, we analyzed the tongue muscle of the transgenic-CuZnSOD mice. The tongue neuromuscular junctions (NMJ) in the transgenic animals exhibited significant pathological changes; withdrawal and destruction of some terminal axons and the development of multiple small terminals. The ratio of terminal axon area to postsynaptic membranes decreased, and secondary folds were often complex and hyperplastic. The morphological changes in the transgenic NMJ were similar to those previously seen in the transgenic NMJ and were similar to those previously seen in muscles of aging mice and rats as well as in tongue muscles of patients with Down's Syndrome. The findings suggest that CuZnSOD gene dosage is involved in the pathological abnormalities of tongue NMJ observed in Down's Syndrome patients.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Cell damage by excess CuZnSOD and Down's syndrome. 799 84

Guam is one of three endemic foci whose indigenous (Chamorro) people have an unusually high incidence of fatal neurodegenerative disorders, amyotrophic lateral sclerosis (ALS) and Parkinsonism-dementia (PD). Recently, mutations in the Cu/Zn superoxide dismutase (SOD-1) gene have been identified in some familial cases of ALS. To investigate if mutations in the SOD-1 gene are also involved in the pathogenesis of ALS and PD of Guam, we analyzed the SOD-1 gene in Chamorros. No mutations were found in Chamorros with ALS or PD, indicating that mutations in the SOD-1 gene do not underlie the high-incidence neurodegenerative disorders of Guam.
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PMID:The Cu/Zn superoxide dismutase gene in ALS and parkinsonism-dementia of Guam. 802 43

Recently, several missense mutations in the Cu/Zn superoxide dismutase gene (SOD1) have been reported as a putative cause of chromosome-21q-linked familial amyotrophic lateral sclerosis (FALS). We have discovered a novel missense mutation (substitution of Thr for Ala4) in exon 1 (GCC to ACC) in two FALS patients from one Japanese FALS family. No mutations were found in 17 cases of sporadic ALS. The enzyme activity of recombinant fusion protein containing the Cu/Zn superoxide dismutase (SOD) with the Ala4-to-Thr mutation was significantly reduced in E. coli. On the other hand, in the expression system in insect cells using Baculovirus, the mutant SOD expressed an enzyme activity as high as wild-type SOD. These results suggest that the stability of SOD with the Ala4-to-Thr mutation is disrupted especially in the fusion protein. Autopsy was carried out on one of the two patients, and the pathological findings were typical of FALS with posterior column involvement. These results raise the possibility that mutation of the SOD1 is responsible for FALS with broader pathological involvement.
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PMID:A novel mutation in Cu/Zn superoxide dismutase gene in Japanese familial amyotrophic lateral sclerosis. 817 2


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