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)

Spinal cords of sporadic cases with amyotrophic lateral sclerosis (ALS) and normal controls were immunohistochemically examined using antibodies for Cu/Zn superoxide dismutase (SOD) and nitrotyrosine (NT). Immunoreactivity for Cu/Zn SOD of the motor neurons was not different between the ALS and controls. In contrast, immunoreactivity for NT was densely detected in motor neurons of ALS but was not or was only minimally detected in those of controls. The staining was also found in the axons of motor neurons of ALS, but was not found in the controls. These results suggest that nitration of protein-tyrosine residue is upregulated in motor neurons of the spinal cord of ALS.
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PMID:Induction of nitrotyrosine-like immunoreactivity in the lower motor neuron of amyotrophic lateral sclerosis. 858 46

The discovery that some cases of familial amyotrophic lateral sclerosis (FALS) are associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) has focused much attention on the function of SOD1 as related to motor neuron survival. Here we describe the creation and characterization of mice completely deficient for this enzyme. These animals develop normally and show no overt motor deficits by 6 months in age. Histological examination of the spinal cord reveals no signs of pathology in animals 4 months in age. However Cu/Zn SOD-deficient mice exhibit marked vulnerability to motor neuron loss after axonal injury. These results indicate that Cu/Zn SOD is not necessary for normal motor neuron development and function but is required under physiologically stressful conditions following injury.
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PMID:Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury. 867 2

A family with autosomal-dominant amyotrophic lateral sclerosis with histopathological confirmation on autopsy was described. A 42-year-old female proband showed the signs and symptoms only in the lower limbs characteristic of lower motor neuron involvement at the onset. ALS had been diagnosed in other five members in three generations of her family. The mean +/- SD age of onset of the disease was 42.5 +/- 9.3 years with a range of 30 to 51 years. The mean +/- SD duration of the disease (n = 5, excluding the proband) was 56 +/- 70 months with a range of 7 to 180 months. Molecular genetic studies showed a T-to-G transversion that results in the substitution of valine for leucine84 in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene on chromosome 21 in a proband. This mutation is identical to that found in the Japanese family with autosomal-dominant ALS characterized by short duration of the disease, within 1.5 years, in all the affected family members. Therefore, the clinical phenotype, especially the duration of the disease seems to be highly variable even in the families with the identical mutation of the Cu/Zn SOD gene.
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PMID:[Familial amyotrophic lateral sclerosis showing variable clinical courses with (Leu84-->Val) mutation of Cu/Zn superoxide dismutase]. 874 55

Amyotrophic lateral sclerosis is a fatal neurodegenerative disorder affecting primarily upper and lower motor neurons. In all cases of ALS, approximately 5-10% of cases are familial (FALS). Missense mutations in the Cu/Zn superoxide dismutase (SOD1) gene on chromosome 21 have been demonstrated in some families of FALS since 1993. We have also identified a novel missense mutation (substitution of Thr for Ala4) in exon 1 in a Japanese FALS family, and clarified the pathological findings of a patient in this family were typical of FALS with posterior column involvement. However, the mechanism by which the mutations in SOD1 lead to ALS is unknown. It is now clear that the mutations in SOD1 reduce total SOD activities only by 30-60%, and there is doubt whether a reduction in enzymatic function of this magnitude suffices to cause the neuronal loss. Recently, transgenic mice expressing the mutant SOD1 demonstrate motor neuron degeneration despite an increased level of SOD activity. The process of motor neuron degeneration in FALS might be mediated by some novel functions of the mutant SOD1 protein.
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PMID:[Familial amyotrophic lateral sclerosis and mutations in the Cu/Zn superoxide dismutase gene]. 875 59

We report clinical characteristics of familial amyotrophic lateral sclerosis (FALS) with 4 different missense point mutations in exons 2, 4, and 5 of the Cu/Zn superoxide dismutase (SOD) gene, that result in amino acid substitutions of histidine46 by arginine (H46R), leucine84 by valine (L84V), isoleucine104 by phenylalanine (I104F), and valine148 by isoleucine (V148I), in 5 Japanese families. Although features of progressive neurogenic muscular atrophy were common in patients of these families, patients of each family showed characteristic clinical features. FALS patients with the H46R mutation showed a benign clinical course and stereotype progression of muscular weakness and atrophy beginning from the legs. In FALS with the L84V mutation, while the clinical course of the disease was similar, the age at onset was younger in men than women. The patients with I104F showed wide ranges of age at onset and duration with ophthalmoparesis and sensory involvement in one patient. Those with the V148I mutation showed younger age at onset and variable first symptoms within the family. Although lower motor sign was evident in all cases, hyperreflexia varied from 0 to 100% among patients with the different mutations, and the Babinski sign was not observed in any case. Bulbar palsy was frequent with I104F, but not with H46R. SOD activity of the red blood cells was severely reduced with I104F and V148I, but was slightly reduced with H46R. These results suggest that familial ALS with different mutations of the Cu/Zn SOD gene each showed clinical characteristics, and that genetic mutations and clinical features are well correlated in familial ALS.
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PMID:Clinical characteristics of familial amyotrophic lateral sclerosis with Cu/Zn superoxide dismutase gene mutations. 881 57

In about 20-25% of cases of familial amyotrophic lateral sclerosis (FALS) patients have mutations in the Cu/Zn superoxide dismutase (SOD1) gene. The mechanism through which the mutations in the SOD1 gene cause ALS still remain unknown. We performed pulse-chase experiments using a system for the transient expression of human SOD1 in COS7 cells to examine whether the Ala4Thr mutation, which we previously reported, decreases the stability of SOD1. The expression vector (pEF-BOS) carrying the wild-type or mutant (Ala4Thr) human SOD1 cDNA was transfected into COS7 cells, and transiently expressed human SOD1 was then metabolically radiolabeled. Half-lives of the wild-type and the Ala4Thr mutant SOD1 were determined to be 78 h and 18 h, respectively. These results suggest that the Ala4Thr mutation in SOD1 decreases the stability of SOD1 and that this instability may play an important role in the pathogenesis of the degeneration of motor neurons in FALS.
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PMID:Instability of mutant Cu/Zn superoxide dismutase (Ala4Thr) associated with familial amyotrophic lateral sclerosis. 883 Aug 61

Point mutations occurring within the Cu/Zn superoxide dismutase (SOD1) gene have been implicated in the etiology of some cases of familial amyotrophic lateral sclerosis (FALS). In order to better understand the functional consequences of these mutations, we have introduced FALS mutations into the mouse SOD1 gene and studied the expression of the mutant templates in stably transformed cell lines. Pulse-chase analyses of lysates derived from cell lines stably expressing the Cu/Zn SOD isoforms indicate that the FALS mutant Cu/Zn SOD proteins are turned over more rapidly than wild-type SOD. Protease inhibitors specific for the major intracellular proteolytic activities were used to characterize the degradative pathways involved in the turnover of mutant Cu/Zn SOD. Inhibition of the chymotrypsin-like activity of the proteasome (also known as multicatalytic proteinase or ubiquitin, ATP-dependent proteinase) by a synthetic dipeptide aldehyde led to a significant increase in levels of the mutant Cu/Zn SOD implicating this proteolytic pathway in the turnover of the FALS mutant SOD proteins.
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PMID:Proteasome inhibition enhances the stability of mouse Cu/Zn superoxide dismutase with mutations linked to familial amyotrophic lateral sclerosis. 883 67

Dominant mutations of human Cu/Zn superoxide dismutase (SOD1) are found in about 20% of patients with familial amyotrophic lateral sclerosis (FALS). A transgenic mouse model of FALS (FALSG93A mice) has been generated by overexpression of a mutated form of SOD1. Using electromyography we first show that FALSG93A mice suffer from motoneurone dysfunction similar to that observed in ALS patients and fulfill Lambert's criteria for ALS. We also showed that FALSG93A mice demonstrate a massive loss of functional motor units starting at 47 days of age. Impairment of motor neurone function preceeds by 6 weeks the onset of apparent clinical signs (shaking, tremor) and the beginning of motor neurone loss. Neuromuscular deficits in FALS mice do not result from motoneuronal cell death but rather from loss of axonal integrity.
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PMID:Neuromuscular function impairment is not caused by motor neurone loss in FALS mice: an electromyographic study. 885 91

Detailed molecular pathology studies and clinicopathological phenotyping of familial amyotrophic lateral sclerosis (FALS) with characterised mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1) will yield important insights into the pathogenesis of motor neuron degeneration. An autopsy case is described with the mutation E100G (exon 4) of the SOD1 gene in which full neuropathological examination including immunocytochemistry of ubiquitin and neurofilament epitopes was performed. The case falls into the category of "amyotrophic lateral sclerosis (ALS) with posterior column involvement." Critical analysis of the findings indicates a truly multisystem disorder in which ascending sensory pathways and components of the efferent cerebellar pathways are at least as severely affected as the motor system. Abnormal neurofilament phosphorylation was not a prominent feature. Ubiquitinated neuronal inclusions were infrequent except in the hippocampal denate granule cells where they were indistinguishable from sporadic cases of ALS-dementia. The motor cortex was preserved despite severe distal axonal loss in the corticospinal tract. These findings suggest a primary failure of axonal maintainance affecting several neuronal groups with long projecting axons. The differences and similarities compared to previously reported case with I113T (exon 4) and A4T (exon 1) mutations are discussed. Findings related to inflammatory cell infiltration, ubiquitination and neurofilament phosphorylation are discussed with reference to the pathogenesis of sporadic ALS.
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PMID:Familial amyotrophic lateral sclerosis with a mutation in exon 4 of the Cu/Zn superoxide dismutase gene: pathological and immunocytochemical changes. 889 Oct 72

We have identified a novel two-base mutation in exon 1 of the Cu/Zn superoxide dismutase (SOD1) gene (TGC to TTT), which resulted in Cys6 to Phe substitution in a Japanese family with amyotrophic lateral sclerosis (ALS). This is the first case of familial ALS-associated two-base change of the SOD1 gene. Similar to several mutations in exon 1 of the SOD1 gene such as Ala4 to Val, Ala4 to Thr and Val14 to Met, affected members of the present family showed a rapid progression of motor dysfunction. Although Ala4, Cys6 and Val7 reside in the middle of the first beta-strand of the SOD1, a family with a mutation of Val7 to Glu associates with slow progression of the disease. These findings suggest that clinical courses are variable with each mutation, even in the same exon.
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PMID:A novel two-base mutation in the Cu/Zn superoxide dismutase gene associated with familial amyotrophic lateral sclerosis in Japan. 890 21


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