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)

A missense mutation (Gly93-->Ser) was identified in exon 4 of the Cu/Zn superoxide dismutase (SOD1) gene of a 48-year-old Japanese man with familial amyotrophic lateral sclerosis (FALS). The SOD1 activities in the fibroblasts and in a lysate of erythrocytes of the patient did not differ from those of healthy controls. The clinical characteristics of the patient were fairly slow progression of the illness, prominent sensory impairment, urinary disturbance and blood pressure fluctuation due to sympathetic hyperactivity. The severe sensory and autonomic disturbances, association of which with FALS has not been previously reported, may represent specific clinical features associated with the Gly93Ser mutation or may indicate the variability of clinical findings even in patients with the same mutation.
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PMID:Prominent sensory and autonomic disturbances in familial amyotrophic lateral sclerosis with a Gly93Ser mutation in the SOD1 gene. 945 83

This investigation deals with the immunocytochemical localization of Cu/Zn superoxide dismutase (SOD) in the spinal cord neurons of transgenic mice that overexpress Gly93Ala mutant human Cu/Zn SOD and demonstrate clinicopathological features similar to human amyotrophic lateral sclerosis (ALS) with Cu/Zn SOD mutation. At low magnification of light microscopy, the gray and white matter of the spinal cord of Gly93Ala mice showed more intense Cu/Zn SOD immunoreactivity than that of control mice. At higher magnification, the cytoplasm of control mice neurons displayed a distinct staining for Cu/Zn SOD, whereas the surrounding neuropil was only weakly stained. In contrast, the intensity of Cu/Zn SOD immunoreactivity in the cytoplasm of the majority of Gly93Ala mice neurons was similar to that in the neuropil. Almost all neuronal hyaline inclusions (NHIs) of Gly93Ala mice were positively immunostained by antibodies to Cu/Zn SOD, ubiquitin and phosphorylated neurofilament protein (NFP), the intensities of which were much higher in the NHIs than in the surrounding cytoplasm. In control mice, significant Cu/Zn SOD precipitation was not observed to be limited to any particular region of the neuronal cytoplasm. Intracytoplasmic vacuoles in the neuronal soma and processes of Gly93Ala mice were not stained by any of these antibodies. These results indicate that Cu/Zn SOD colocalizes with ubiquitin and phosphorylated NFP in NHIs of mice expressing mutant Cu/Zn SOD; similar findings have been shown for Lewy body-like inclusions of familial ALS patients with Cu/Zn SOD mutation. Moreover, our results point to the possibility that Cu/Zn SOD mutation may have a role in the abnormal Cu/Zn SOD accumulation in the NHIs, in association with motor neuron degeneration.
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PMID:Presence of Cu/Zn superoxide dismutase (SOD) immunoreactivity in neuronal hyaline inclusions in spinal cords from mice carrying a transgene for Gly93Ala mutant human Cu/Zn SOD. 949 47

The ALS1 (agglutinin-like sequence) gene of Candida albicans encodes a protein similar to alpha-agglutinin, a cell-surface adhesion glycoprotein of Saccharomyces cerevisiae (Hoyer et al. 1995). A central domain of a tandemly repeated 108-bp sequence is found in the ALS1 coding region. This tandem-repeat motif hybridizes to multiple C. albicans genomic DNA fragments, indicating the possibility of other ALS1-like genes in C. albicans (Hoyer et al. 1995). To determine if these fragments constitute a gene family, tandem-repeat-hybridizing genomic fragments were isolated from a fosmid library by PCR screening using primers based on the consensus tandem-repeat sequence of ALS1 (Hoyer et al. 1995). One group of fosmids, designated ALS3, encodes a gene with 81% identity to ALS1. The sequences of ALS1 and ALS3 are most conserved in the tandem-repeat domain and in the region 5' of the tandem repeats. Northern-blot analysis using unique probes from the 3' end of each gene demonstrated that ALS1 expression varies, depending on which C. albicans strain is examined, and that ALS3 is hyphal-specific. Both genes are found in a variety of C. albicans and C. stellatoidea strains examined. The predicted Als1p and Als3p exhibit features suggesting that both are cell-surface glycoproteins. Southern blots probed with conserved sequences from the region 5' of the tandem repeats suggest that other ALS-like sequences are present in the C. albicans genome and that the ALS family may be larger than originally estimated.
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PMID:Candida albicans ALS3 and insights into the nature of the ALS gene family. 964 9

Autosomal dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Previous studies have implicated the involvement of metabolic dysfunction in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined SOD activity and mitochondrial oxidative phosphorylation enzyme activities 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). Cytosolic SOD activity, predominantly Cu/Zn SOD, was decreased approximately 50% in all regions in FALS patients with SOD mutations but was not significantly altered in other patient groups. Marked increases in complex I and II-III activities were seen in FALS patients with SOD mutations but not in SALS patients. We also measured electron transport chain enzyme activities in a transgenic mouse model of FALS. Complex I activity was significantly increased in the forebrain of 60-day-old G93A transgenic mice overexpressing human mutant SOD1, relative to levels in transgenic wild-type animals, supporting the hypothesis that the motor neuron disorder associated with SOD1 mutations involves a defect in mitochondrial energy metabolism.
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PMID:Metabolic dysfunction in familial, but not sporadic, amyotrophic lateral sclerosis. 964 76

Mutations in Cu/Zn superoxide dismutase (SOD1) cause a subset of cases of familial amyotrophic lateral sclerosis (FALS). We established a simple and defined method to detect the mutant SODI in erythrocytes by electrospray ionization mass spectrometry (ESIMS) using materials precipitated with specific antiserum. Hemolysate was mixed with anti-SOD1 antiserum and the generated precipitate, which was soluble in the solvent for MS analysis, was injected on to an LC column connected to an ESI-mass spectrometer. MS spectra of the reduced SOD1 prepared from normal individuals showed ion peaks corresponding to free monomer SOD1. The spectra from FALS patients revealed doublet ion peaks corresponding to normal and mutant components. The ratios of mutant to normal SOD1 were about 1/2 in cases of (G37R) and (A4S), and about 0.15 in a case of (H46R). This method provides for the rapid diagnosis using small amount of specimens, and will contribute to elucidate the pathomechanism of FALS through the quantification of SOD1 mutants in erythrocytes and in tissues of nervous systems.
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PMID:Simple and defined method to detect the SOD-1 mutants from patients with familial amyotrophic lateral sclerosis by mass spectrometry. 969 8

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the premature death of motor neurons. In approximately 10% of the cases the disease is inherited as autosomal dominant trait (FALS). It has been found that mutations in the Cu/Zn superoxide dismutase gene (SOD1) are responsible for approximately 15% of FALS kindreds. We screened affected individuals from 70 unrelated FALS kindreds and identified 10 mutations, 6 of which are novel. Surprisingly, we have found a mutation in exon 3, which includes most of the active site loop and Zn2+ binding sites, a region where no previous SOD1 mutations have been found. Our data increase the number of different SOD1 mutations causing FALS to 55, a significant fraction of the 154 amino acids of this relatively small protein.
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PMID:Identification of six novel SOD1 gene mutations in familial amyotrophic lateral sclerosis. 970 19

Additional genes in the growing ALS family of Candida albicans were isolated by PCR screening of a genomic fosmid library with primers designed from the consensus tandem-repeat sequence of ALS1. This procedure yielded fosmids encoding ALS2 and ALS4. ALS2 and ALS4 conformed to the three-domain structure of ALS genes, which consists of a central domain of tandemly repeated copies of a 108-bp motif, an upstream domain of highly conserved sequences, and a domain of divergent sequences 3' of the tandem repeats. Alignment of five predicted Als protein sequences indicated conservation of N- and C-terminal hydrophobic regions which have the hallmarks of secretory signal sequences and glycosylphosphatidylinositol addition sites, respectively. Heterologous expression of an N-terminal fragment of Als1p in Saccharomyces cerevisiae demonstrated function of the putative signal sequence with cleavage following Ala17. This signal sequence cleavage site was conserved in the four other Als proteins analyzed, suggesting identical processing of each protein. Primary-structure features of the five Als proteins suggested a cell-surface localization, which was confirmed by indirect immunofluorescence with an anti-Als antiserum. Staining was observed on mother yeasts and germ tubes, although the intensity of staining on the mother yeast decreased with elongation of the germ tube. Similar to other ALS genes, ALS2 and ALS4 were differentially regulated. ALS4 expression was correlated with the growth phase of the culture; ALS2 expression was not observed under many different in vitro growth conditions. The data presented here demonstrate that ALS genes encode cell-surface proteins and support the conclusion that the size and number of Als proteins on the C. albicans cell surface vary with strain and growth conditions.
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PMID:Identification of Candida albicans ALS2 and ALS4 and localization of als proteins to the fungal cell surface. 976 64

A replication-defective recombinant adenoviral vector containing E. coli lacZ gene was injected into the right biceps brachii muscles of transgenic mice carrying mutant human Cu/Zn superoxide dismutase (SOD1) gene and non-transgenic wild-type mice at 27 weeks of age. Although the transgenic mice showed remarkable neurogenic muscular changes and a marked motor neuron loss in the anterior horn of spinal cord, the lacZ gene was widely expressed in all the injected muscles of transgenic mice as well as of wild-type mice at 7 days after the injection. In one transgenic and two wild-type mice, the lacZ gene expression was first detected in a few motor neurons of right lower cervical cord (C5-C6). These results demonstrate that an adenovirus-mediated foreign gene is transferred and expressed in skeletal muscles both of normal and transgenic mice model for familial amyotrophic lateral sclerosis (FALS), and also, in the spinal motor neurons, may be transferred by retrograde transport from innervated muscles.
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PMID:Expression of adenovirus-mediated E. coli lacZ gene in skeletal muscles and spinal motor neurons of transgenic mice with a mutant superoxide dismutase gene. 979 15

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurological disorder of multiple etiologies that affects primarily motor neurons in the brain and spinal cord. Abnormal accumulations of neurofilaments (NFs) in motor neurons and a down-regulation of mRNA for the NF light subunit (NF-L) are associated with ALS, but it remains unclear to what extent these NF perturbations contribute to human disease. Transgenic mouse studies demonstrated that overexpression of normal and mutant NF proteins can sometimes provoke a motor neuronopathy characterized by the presence of abnormal NF accumulations resembling those found in ALS. Remarkably, the motor neuronopathy in transgenic mice overexpressing human NF heavy (NF-H) subunits was rescued by the co-expression of a human NF-L transgene at levels that restored a correct stoichiometry of NF-L to NF-H subunits. Transgenic approaches have also been used to investigate the role of NFs in disease caused by Cu/Zn superoxide dismutase (SOD1) mutations, which is responsible for approximately 2% cases of ALS. Studies with transgenic mice expressing low levels of a fusion NF-H/lacZ protein, in which NFs are withheld from the axonal compartment, suggested that axonal NFs are not toxic intermediates required for SOD1-mediated disease. On the contrary, overexpression of human NF-H proteins was found to confer an effective protection against mutant SOD1 toxicity in transgenic mice, a phenomenon that may be due to the ability of NF proteins to chelate calcium. In conclusion, transgenic studies showed that disorganized NFs can sometimes have noxious effects resulting in neuronopathy. However, in the context of motor neuron disease caused by mutant SOD1, there is emerging evidence that NF proteins rather play a protective role.
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PMID:Transgenic mice in the study of ALS: the role of neurofilaments. 980 82

To investigate the molecular mechanisms of the 'gain of toxic function' of mutant Cu/Zn superoxide dismutase (SOD) associated with familial amyotrophic lateral sclerosis (FALS), mutant (Ala 4 --> Thr, Gly 85 --> Arg, Gly 93 --> Ala, and two base-pair deletion in the 126th codon), as well as wild-type (wt), Cu/Zn SODs were expressed in COS7 cells. The formation of granular cytoplasmic aggregates accompanied by collapse of the cytoplasm was observed in cells expressing mutant (mt) Cu/Zn SODs, but not in cells expressing wt Cu/Zn SOD. The aggregates contained ribosome-like particles and endoplasmic reticulum. These results suggest the possibility that mt Cu/Zn SODs promote the formation of aggregates which are toxic to cells.
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PMID:Formation of granular cytoplasmic aggregates in COS7 cells expressing mutant Cu/Zn superoxide dismutase associated with familial amyotrophic lateral sclerosis. 985 58


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