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)

Neurofilament pathology is a hallmark of sporadic and familial amyotrophic lateral sclerosis (SALS and FALS). The disease mechanisms underlying this pathology are presently unclear, but recent evidence in SALS patients suggest that reductions in neurofilament light subunit (NFL) mRNA may contribute to the death of motor neurones. Mutations in the gene encoding Cu-Zn superoxide dismutase (SOD1) represent the best-studied cause of FALS, and a number of laboratory models of SOD1-mediated disease exist. Here we have used microdissected lumbar spinal cord motor neurones from human SOD1 FALS patients as well as G93A SOD1 transgenic mice and demonstrated that reduced NFL mRNA levels are seen in both. To probe the molecular mechanisms underpinning these observations, we generated NSC34 motor neurone-like cell lines expressing wild-type and mutant SOD1. NSC34 cells expressing G37R or G93A SOD1 showed selective reductions in NFL and NFM mRNA and protein. These data suggest that NFL mRNA reductions are common to SALS and FALS patients, and that cells and mice expressing mutant SOD1 may enable us to characterize the molecular mechanism(s) responsible for the loss of neurofilament mRNA.
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PMID:Selective loss of neurofilament expression in Cu/Zn superoxide dismutase (SOD1) linked amyotrophic lateral sclerosis. 1235 59

Amyotrophic lateral sclerosis (ALS) is a fatal adult-onset disease in which motor neurons in the brain and spinal cord degenerate by largely unknown mechanisms. ALS is familial (FALS) in 10% of cases, and the inheritance is usually dominant, with variable penetrance. Mutations in copper/zinc super oxide dismutase (SOD1) are found in 20% of familial and 3% of sporadic ALS cases. Five families with ALS and frontotemporal dementia (ALS-FTD) are linked to 9q21, whereas one family with pure ALS is linked to 18q21. We identified two large European families with ALS without SOD1 mutations or linkage to known FALS loci and conducted a genomewide linkage screen using 400 microsatellite markers. In both families, two-point LOD scores >1 and a haplotype segregating with disease were demonstrated only across regions of chromosome 16. Subsequent fine mapping in family 1 gave a maximum two-point LOD score of 3.62 at D16S3137 and a three-point LOD score of 3.85 for markers D16S415 and D16S3137. Haplotype analysis revealed no recombination > approximately 30 cM, (flanking markers at D16S3075 and D16S3112). The maximum two-point LOD score for family 2 was 1.84 at D16S415, and the three-point LOD score was 2.10 for markers D16S419 and D16S415. Definite recombination occurred in several individuals, which narrowed the shared haplotype in affected individuals to a 10.1-cM region (flanking markers: D16S3396 and D16S3112). The region shared by both families on chromosome 16q12 corresponds to approximately 4.5 Mb on the Marshfield map. Bioinformatic analysis of the region has identified 18 known genes and 70 predicted genes in this region, and sequencing of candidate genes has now begun.
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PMID:Two families with familial amyotrophic lateral sclerosis are linked to a novel locus on chromosome 16q. 1284 Jul 84

Glutamate excitotoxicity is implicated in the aetiology of amyotrophic lateral sclerosis (ALS) with impairment of glutamate transport into astrocytes a possible cause of glutamate-induced injury to motor neurons. It is possible that mutations of Cu/Zn superoxide dismutase (SOD1), responsible for about 20% of familial ALS, down-regulates glutamate transporters via oxidative stress. We transfected primary mouse astrocytes to investigate the effect of the FALS-linked mutant hSOD1(G93A) and wild-type SOD1 (hSOD1wt) on the glutamate uptake system. Using western blotting, immunocytochemistry and RT-PCR it was shown that expression of either hSOD1(G93A) or hSOD1wt in astrocytes produced down-regulation of the levels of a glutamate transporter GLT-1, without alterations in its mRNA level. hSOD1(G93A) or hSOD1wt expression caused a decrease of the monomeric form of GLT-1 without increasing oxidative multimers of GLT-1. The effects were selective to GLT-1, since another glutamate transporter GLAST protein and mRNA levels were not altered. Reflecting the decrease in GLT-1 protein, [3H]d-aspartate uptake was reduced in cultures expressing hSOD1(G93A) or hSOD1wt. The hSOD1-induced decline in GLT-1 protein and [3H]d-aspartate uptake was not blocked by the antioxidant Trolox nor potentiated by antioxidant depletion using catalase and glutathione peroxidase inhibitors. Measurement of 2',7'-dichlorofluorescein (DCF)-induced fluorescence revealed that expression of hSOD1(G93A) or hSOD1wt in astrocytes does not lead to detectable increase of intracellular reactive oxygen species. This study suggests that levels of GLT-1 protein in astrocytes are reduced rapidly by overexpression of hSOD1, and is due to a property shared between the wild-type and G93A mutant form, but does not involve the production of intracellular oxidative stress.
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PMID:Expression of SOD1 G93A or wild-type SOD1 in primary cultures of astrocytes down-regulates the glutamate transporter GLT-1: lack of involvement of oxidative stress. 1469 May 36

About 20 p. cent of cases of amyotrophic lateral sclerosis are familial (FALS). Fifteen percent of FALS cases are associated with an abnormality in the superoxide dismutase 1 (SOD1) gene. To date, more than 100 different genetic abnormalities have been reported, all except two are autosomal dominant. The clinical characteristics of patients presenting with FALS associated with an SOD1 abnormality is homogeneous when there is no doubt about the hereditary aspect of the genetic abnormality: mean age at onset 42 years, limb onset, slow evolution. Except when present in the setting of a clearly inherited disease (FALS) (several patients through several generations), the causality of a given SOD1 mutation often remains an open question. Consequently, search for SOD1 mutation is not warranted when atypical features such as young age at onset or slow progression are present. Conversely, a complete family study is justified to determine the precise role of a given SOD1 mutation because of the large number of potential SOD1 mutations, the variability of the transmission mode, and the non-exceptional absence of proven causality for ALS. Specific cases where a frequent SOD1 mutation with a recognized causal effect is recognized (no more than 15 out of more than 90 mutations) would be an exception.
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PMID:[Superoxyde dismutase 1 gene abnormalities in familial amyotrophic lateral sclerosis: phenotype/genotype correlations. The French experience and review of the literature]. 1497 93

Literature findings on astrogliosis of the spinal cord and of the cortex of sporadic (SALS) and familial (FALS) cases of amyotrophic lateral sclerosis (ALS) and of SOD1 transgenic mice are analysed and compared with those of 50 autopsied personal cases of ALS. In the spinal cord, astrogliosis is definitely evident in the anterior horns and much less in anterior and lateral funiculi and dorsal horns. In the cortex reactive astrocytes show a distribution similar to that of ageing brains and in ischaemia and cannot be directly put in relation with neuronal loss. In the spinal cord of transgenic mice the evidence suggests a primary astrocytic response. The findings in human ALS, especially those of the cortex, are consistent with this hypothesis.
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PMID:Astrogliosis in ALS: possible interpretations according to pathogenetic hypotheses. 1520 20

Amyotrophic lateral sclerosis (ALS) is a lethal degenerative motor neuron disease. Approximately, 5-10% of cases of ALS are familial (FALS), inherited primarily as an autosomal dominant trait. Recently, mutations in Cu/Zn superoxide dismutase (SOD1) have been identified; 15-20% of familial cases carry this mutation, providing a marker for diagnosis, carrier testing, and prenatal detection. We assessed understanding of genetics of FALS in relatives of patients cared for at the Forbes Norris MDA/ALS Research Center in San Francisco. A total of 25 participants completed a questionnaire and semistructured interview. Of these, 60% would have gene testing for themselves; 36% believed testing of children or adolescents was a good idea. Overall knowledge of genetics of FALS was limited. Also, 24% of respondents understood the inheritance pattern of FALS; 64% were aware that not all individuals who had the gene would show symptoms in their lifetime. Families were confused about whether they would receive results from linkage studies. We recommend that: (1) physicians refer relatives of newly diagnosed individuals for genetic counseling and possibly psychological counseling; (2) investigators ensure that participants comprehend the purpose of gene identification is for research, not disclosure of individual results; (3) families be helped to understand how to keep abreast of medical and genetic advances; (4) following the model of Huntington disease (HD), consensus guidelines for FALS genetic counseling and testing be developed.
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PMID:"You have shown me my end": attitudes toward presymptomatic testing for familial amyotrophic lateral sclerosis. 1532 23

Amyotrophic Lateral Sclerosis (ALS), the most common form among motoneuron diseases, is characterized by a progressive neurodegenerative process involving motor neurons in the motor cortex, brain stem and spinal cord. Sporadic (SALS) accounts for the majority of patients but in about 10% of ALS cases the disease is inherited (FALS), usually as an autosomal dominant trait. In the present study we show the results of a referred based multicenter study on the distribution of SOD1 gene mutations in the largest cohort of Italian ALS patients described so far. Two hundred and sixty-four patients (39 FALS and 225 SALS) of Italian origin were studied. In 7 out of 39 FALS patients we found the following SOD1 gene mutations: i) a new G12R missense mutation in exon 1, found in a patient with a slowly progressive disease course; ii) the G41S mutation, in four unrelated patients with rapidly progressive course complicated with cognitive decline in two of them; iii) the L114F mutation, in a patient with a slowly progressive phenotype; iv) the D90A mutation, in a heterozygous patient with atypical phenotype. In addition, in one SALS patient a previously reported synonymous variant S59S was identified. In 17 (3 FALS and 14 SALS) out of 264 patients (6.4 %) the polymorphism A-->C at position 34 of intron 3 (IVS3: + 34 A-->C) was found, and in one FALS patient a novel variant IVS3 + 62 T-->C was identified. The frequency of SOD1 gene mutations (17.9 %) in FALS cases was comparable with that found in other surveys with a similar sample size of ALS cases. No SOD1 gene mutations have been identified in SALS cases. Within FALS cases, The most frequent mutation was the G41S identified in four FALS.
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PMID:SOD1 mutations in amyotrophic lateral sclerosis. Results from a multicenter Italian study. 1578 35

Amyotrophic lateral sclerosis (ALS) is an adult-onset degenerative disorder characterised by the death of motor neurons in the cortex, brainstem, and spinal cord; resulting in progressive muscle weakness, atrophy, and death from respiratory paralysis, usually within 3-5 years of symptom onset. Approximately 10% of ALS cases are familial (FALS). Mutations in superoxide dismutase-1 (SOD1) cause approximately 20% of FALS cases and there is overwhelming evidence that a toxic gain of function is the cause of the disease. We have previously shown that FALS-associated SOD1 disease mutants enhanced neuronal death in response to a wide range of stimuli tested whereas wt-SOD1 protected against all insults. We demonstrate for the first time that over-expression of either heat shock protein Hsp27 or Hsp70 has a protective effect against SOD1 disease associated mutant-induced cell death. However, over-expression of Hsp27 and Hsp70 together has a greater potent anti-apoptotic effect, than when expressed singly, against the damaging effects of mutant SOD1. Our results indicate that FALS-associated SOD1 disease mutants possess enhanced death-inducing properties and lead to increased apoptosis which can be prevented by either the use of specific caspase inhibitors or Hsp27 and/or Hsp70 over-expression. This potent protective effect of Hsp27 and Hsp70 against the FALS-associated SOD1 disease mutants may be of potential therapeutic importance.
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PMID:Hsp27 and Hsp70 administered in combination have a potent protective effect against FALS-associated SOD1-mutant-induced cell death in mammalian neuronal cells. 1583 22

Amyotrophic lateral sclerosis (ALS) is caused by mutations in the gene for Cu/Zn superoxide dismutase (SOD1) in 10% of familial and sporadic cases. During the SOD1 analysis of 9 FALS and 121 SALS, in only one sporadic case we found the exonic mutation N19S; in 15 SALS patients we found a 319t>a variation in IVS1 sequence, at 108 bp upstream from exon 2. This variation has an unusually high frequency of 11% and is always in linkage disequilibrium with a described polymorphism in IVS3, +34a>c. The 319t>a variation is classified in two different public databases, HGMD and The ALS Online Database, as a splicing mutation and not as a polymorphism. The unusually high frequency of this mutation in our patients prompted us to determinate its frequency in 130 age- and gender- matched healthy controls and in 54 patients with Alzheimer's disease. We found again linkage disequilibrium with the polymorphism in intron 3, and the frequency of 11% and 7.8%, respectively. These results strongly support the idea that the IVS1 +319 t>a alone is not an ALS causing mutation, and that special care must be taken in the interpretation of data from mutations databases for correct genetic counselling.
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PMID:The IVS1 +319 t>a of SOD1 gene is not an ALS causing mutation. 1603 25

Approximately 10% of amyotrophic lateral sclerosis (ALS) cases are familial (FALS), and approximately 25% of FALS cases are caused by mutations in superoxide dismutase-1 (SOD1). Mutant (MT) SOD1 kills motor neurons because of the mutant protein's toxicity; however, the basis for toxicity is unknown. We electroporated wild-type (WT), truncated WT or MTSOD1 expression constructs into the chick embryo spinal cord. MTSOD1 and truncated WTSOD1 (as small as 36 amino acid residues in length) aggregated in the cytoplasm of cells and caused cell death. These results suggest that MTSOD1 and truncated WTSOD1 lead to neural cell death because of misfolding, and that SOD1 peptides, possibly as a result of proteolytic digestion of MTSOD, play a role in FALS pathogenesis. Electroporation of the chick embryo spinal cord is a useful system in which to investigate neurodegenerative diseases because it provides efficient delivery of genes into neural cells in situ within a living organism.
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PMID:Truncated wild-type SOD1 and FALS-linked mutant SOD1 cause neural cell death in the chick embryo spinal cord. 1608 30


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