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 dramatic loss of glutamate transport has been observed in sporadic amyotrophic lateral sclerosis and has been postulated to contribute to the disease. Experimentally, this hypothesis was corroborated by mimicking the chronic loss of glutamate transport in postnatal rat spinal cord organotypic cultures through the use of glutamate transport inhibitors. This system is characterized by a relatively selective slow loss of ventral horn motor neurons resulting from glutamate transport inhibition. In this study, spinal cord organotypic cultures were used to test various drugs to evaluate their neuroprotective properties against this slow glutamate-mediated neurotoxicity The most potent neuroprotectants were drugs that altered glutamate neurotransmission, including non-NMDA receptor antagonists (GYKI-52466, PD144216, and PD13997) and drugs that could block presynaptic release or synthesis (riluzole and gabapentin). In addition, some antioxidants (U83836E and N-t-butyl-alpha-phenylnitrone) and inhibitors of nitric oxide synthesis (NG-monomethyl-L-arginine acetate) were modestly neuroprotective. The calcium endonuclease inhibitor aurintricarboxylic acid and the calcium release inhibitor dantrolene also provided partial motor neuron protection. However, several antioxidants and calcium channel antagonists had no excitotoxic neuroprotectant activity. This system provides a preclinical screening method for the burgeoning number of drugs postulated for clinical trials in motor neuron disease and a model to evaluate the mechanisms of chronic glutamate toxicity.
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PMID:Neuroprotective strategies in a model of chronic glutamate-mediated motor neuron toxicity. 761 20

Among the more frequent oxidative DNA injuries is the formation of abasic sites (AP sites) resulting from removal of purine or pyrimidine bases, estimated to occur at a rate of 1 x 10(4)/genome/24 h. A defect in DNA repair at this level could account for the accumulation of mutations and subsequent genome instability. We have identified missense mutations in the APE gene coding for a multifunctional DNA repair enzyme, AP endonuclease in eight of 11 patients with amyotrophic lateral sclerosis (ALS) and familial ALS. These mutations could affect the repair of abasic sites leading to the accumulation of mutations in neurons, resulting in their degeneration and death. Our findings implicate mutated AP endonuclease in the pathogenesis of ALS.
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PMID:Mutant AP endonuclease in patients with amyotrophic lateral sclerosis. 950 62

With a 0.5 kb probe of CX2, distribution of CX2 tandem repeats was studied in different C.albicans strains. Results suggest that all the C.albicans strains tested contained the tandem repeat. In order to verify if the expression of CX2 was hyphal specific, its expression was analyzed under various inductive and non-inductive conditions. With CX2 0.5 kb probe, Northern hybridization analysis confirmed that it was specifically in hyphae. The result of chromosomal localizationtion and genomic Southern blot analysis suggested that there were other genes containing the tandem repeat besides of ALS1. A C.albicans s genomic DNA library was screened with the CX2 0.5 kb probe and several positive recombinant lambda phages were obtained. After endonuclease identification, subcloning, and sequence analysis, several ALS family genes were cloned. No.1 lambda phage DNA contained ALS4, No.4 lambda phage DNA contained ALS1, No.6 lambda phage DNA contained ALS3. To study the role of ALS family genes in yeast-hyphal transition, als1/ALS1 mutant was constructed by homologous recombination. The ability to form hyphae was tested in different inductive culturing conditions. Defective hyphal growth were observed in some solid media.
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PMID:Cloning and Functional Analysis of ALS Family Genes from Candida albicans. 1205 69

A novel mutation of the SOD-1 gene which encodes the enzyme copper-zinc superoxide dismutase was identified in a family manifesting amyotrophic lateral sclerosis (ALS) in three generations. The mutation is a heterozygote point mutation in exon 4, codon 108 (GGA to GTA), predicting the substitution of valine for glycine. The mutation creates a new restriction site for the endonuclease AccI. The mutation was demonstrated in two affected members of the family, who show features of autosomal dominant inheritance of ALS, but variable age at onset ranging from 48 to 72 years. Over 30 different mutations of SOD-1 have now been identified in families with ALS. The definition of the different mutations causing human disease may allow further investigation of their pathogenicity in transgenic animal models, and also offers insight into the variable phenotypic disease expression both within and between genotypes.
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PMID:A novel mutation of SOD-1 (Gly 108 Val) in familial amyotrophic lateral sclerosis. 2428 21

Long interspersed element-1 (LINE-1/L1) is the only autonomous transposable element in the human genome that currently mobilises in both germline and somatic tissues. Recent studies have identified correlations between altered retrotransposon expression and the fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) in a subset of patients. The risk of an individual developing ALS is dependent on an interaction of genetic variants and subsequent modifiers during life. These modifiers could include environmental factors, which can lead to epigenetic and genomic changes, such as somatic mutations, occurring in the neuronal cells that degenerate as the disease develops. There are more than 1 million L1 copies in the human genome today, but only 80-100 L1 loci in the reference genome are considered to be retrotransposition-competent (RC) and an even smaller number of these RC-L1s loci are highly active. We hypothesise that RC-L1s could affect normal cellular function through their mutagenic potential conferred by their ability to retrotranspose in neuronal cells and through DNA damage caused by the endonuclease activity of the L1-encoded ORF2 protein. To investigate whether either an increase in the genomic burden of RC-L1s or epigenetic changes to RC-L1s altering their expression, could play a role in disease development, we chose a set of seven well characterised genomic RC-L1 loci that were reported earlier to be highly active in a cellular L1 retrotransposition reporter assay or serve as major source elements for germline and/or somatic retrotransposition events. Analysis of the insertion allele frequency of five polymorphic RC-L1s, out of the set of seven, for their presence or absence, did not identify an increased number individually or when combined in individuals with the disease. However, we did identify reduced levels of methylation of RC-L1s in the motor cortex of those individuals with both familial and sporadic ALS compared to control brains. The changes to the regulation of the loci encompassing these RC-L1s demonstrated tissue specificity and could be related to the disease process.
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PMID:Frequency and methylation status of selected retrotransposition competent L1 loci in amyotrophic lateral sclerosis. 3318 50