Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Demonstration of a genetic linkage between the Cu/Zn superoxide dismutase (SOD1) gene and familial amyotrophic lateral sclerosis (ALS) has aroused interest in the role of SOD1 in spinal motoneuronal death. We used chronically beta,beta'-iminodipropionitrile (IDPN)-intoxicated rats as a model of ALS and investigated SOD1 changes in the spinal cord by immunocytochemical and in situ hybridization techniques. Compared with control rats, SOD1-like immunoreactivity (SOD1-IR) increased in swollen axons of the proximal spinal roots, but not in motoneuronal and dorsal root ganglion neuronal cell bodies where SOD1 gene transcription did not increase. The present data indicate that treatment with IDPN induces accumulation of SOD1 in the swollen axons by blocking slow axonal flow, suggesting the possibility that increased SOD1-IR in ALS is induced by axonal flow blockade.
 ...
PMID:Increased Cu/Zn superoxide dismutase-like immunoreactivity in the swollen axons of rats intoxicated chronically with beta,beta'-iminodipropionitrile. 747 39

About 10% of cases of amyotrophic lateral sclerosis (ALS), a paralytic disorder characterized by death of motor neurons in the brain and spinal cord, exhibit autosomal dominant inheritance. A subgroup of these familial cases are caused by mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). We report here three additional mutations occurring in the SOD1 gene in three families with ALS. Two of these changes are missense mutations in exon 5 of the SOD1 gene, resulting in leucine 144 to serine and alanine 145 to threonine substitutions. The third, a single base pair change in intron 4 immediately upstream of exon 5, results in an alternatively spliced mRNA. The alternate transcript conserves the open reading frame of exon 5, producing an SOD1 protein with three amino acids inserted between exons 4 and 5 (following residue 118). These three mutations bring to 29 the total number of distinct SOD1 mutations associated with familial ALS.
 ...
PMID:Identification of three novel mutations in the gene for Cu/Zn superoxide dismutase in patients with familial amyotrophic lateral sclerosis. 749 69

Gene mutations of Cu/Zn superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Oxidative stress also plays a role in the pathogenesis of sporadic ALS. Whether antioxidant therapy is beneficial in this fatal disease is now crucial. We have shown that SOD treatment improves neuromuscular dysfunction and morphological changes in wobbler mouse motoneuron disease. Progressive spinal motor neuronopathy and axonopathy, predominantly in the cervical cord, occur at postnatal age 3-4 weeks, leading to muscle weakness and contracture of the forelimbs in this animal. These motor deficits rapidly increase by postnatal age 6-8 weeks, and then slowly progress. Wobbler mice were given two doses daily of phosphatidyl choline-bound Cu/Zn SOD (PC-SOD, 10(4), 10(5) U/kg) or a vehicle solution by intraperitoneal injection from postnatal 3-4 to postnatal 7-8 weeks of age. PC-SOD treatment attenuated progression of motor dysfunction, prevented denervation muscle atrophy, and delayed degeneration of spinal motoneurons in wobbler mice. This raises the possibility that PC-SOD may have therapeutic potential in human motoneuron disease.
 ...
PMID:Lecithinized superoxide dismutase retards wobbler mouse motoneuron disease. 749 72

We report a novel missense point mutation in exon 4 of the Cu/Zn superoxide dismutase (SOD) gene of affected members of a Japanese kindred segregating familial amyotrophic lateral sclerosis (FALS) through at least three successive generations. The mutation, which is predicted to cause the replacement of isoleucine at codon 104 by phenylalanine (I104F), is associated with a significant reduction in Cu/Zn SOD enzyme activity but results in a highly variable clinical phenotype. Age at onset varied from 6 to 55; the initial symptoms occurred in either the lower or upper extremities in different family members. The duration of the disease varied from 3 to 38 years. Two subjects, aged 59 and 34, remained asymptomatic until their death from other causes, although their offspring carrying the same mutation have already developed clinical evidence of the disease. These results suggest that FALS from this novel I104F mutation shows considerable clinical variation.
 ...
PMID:Variable clinical symptoms in familial amyotrophic lateral sclerosis with a novel point mutation in the Cu/Zn superoxide dismutase gene. 750 Nov 56

Point mutations in the cytosolic Cu/Zn superoxide dismutase (SOD-1) gene have been detected in association with familial amyotrophic lateral sclerosis (FALS). SOD clears superoxide radical and is one of the body's principal defense mechanisms against oxygen toxicity. The finding of SOD variants in FALS is consistent with the hypothesis that free radicals contribute to the pathogenesis of FALS, and possibly to the pathogenesis of other neurodegenerative disorders such as Parkinson's disease, in which there is substantial evidence of oxidant stress. The implication of free radicals in the pathogenesis of neurodegenerative disorders raises the possibility that antioxidants might provide neuroprotective therapy.
 ...
PMID:A radical hypothesis for neurodegeneration. 752 Feb

Mutations in Cu/Zn superoxide dismutase (SOD), a hallmark of familial amyotrophic lateral sclerosis (FALS) in humans, are shown here to confer striking neuropathology in Drosophila. Heterozygotes with one wild-type and one deleted SOD allele retain the expected 50% of normal activity for this dimeric enzyme. However, heterozygotes with one wild-type and one missense SOD allele show lesser SOD activities, ranging from 37% for a heterozygote carrying a missense mutation predicted from structural models to destabilize the dimer interface, to an average of 13% for several heterozygotes carrying missense mutations predicted to destabilize the subunit fold. Genetic and biochemical evidence suggests a model of dimer dysequilibrium whereby SOD activity in missense heterozygotes is reduced through entrapment of wild-type subunits into unstable or enzymatically inactive heterodimers. This dramatic impairment of the activity of wild-type subunits in vivo has implications for our understanding of FALS and for possible therapeutic strategies.
 ...
PMID:Subunit-destabilizing mutations in Drosophila copper/zinc superoxide dismutase: neuropathology and a model of dimer dysequilibrium. 756 70

The discovery of mutations in the gene for Cu/Zn superoxide dismutase (SOD) in some cases of familial amyotrophic lateral sclerosis (FALS) provides a rationale for enzyme replacement therapy. The inability of SOD to cross the blood-brain barrier motivated this study of the safety, tolerability and pharmacokinetics of bovine SOD (bSOD) administered into the CSF of rhesus monkeys and one late-stage, SOD-deficient FALS patient. Kinetic analyses in the patient indicated that intracerebroventricular (i.c.v.) administration, but not lumbar administration, delivered bSOD to the entire CSF pathway. Daily bolus i.c.v. injections (32 mg/day) and continuous i.c.v. infusion (30 mg/day) were well tolerated by the patient. During the period of daily bolus injections, the patient's performance on manual muscle tests was nearly stable, in contrast with the rapid decline before and after that period. These results justify further investigation of bSOD therapy in SOD-deficient FALS patients.
 ...
PMID:Pharmacokinetics and tolerability of ventricularly administered superoxide dismutase in monkeys and preliminary clinical observations in familial ALS. 759 4

Mutations in Cu/Zn superoxide dismutase (SOD1) cause a subset of cases of familial amyotrophic lateral sclerosis. Four lines of mice accumulating one of these mutant proteins (G37R) develop severe, progressive motor neuron disease. At lower levels of mutant accumulation, pathology is restricted to lower motor neurons, whereas higher levels cause more severe abnormalities and affect a variety of other neuronal populations. The most obvious cellular abnormality is the presence in axons and dendrites of membrane-bounded vacuoles, which appear to be derived from degenerating mitochondria. Since multiple lines of mice expressing wild-type human SOD1 at similar and higher levels do not show disease, the disease in mice expressing the G37R mutant SOD1 must arise from the acquisition of an adverse property by the mutant enzyme, rather than elevation or loss of SOD1 activity.
 ...
PMID:An adverse property of a familial ALS-linked SOD1 mutation causes motor neuron disease characterized by vacuolar degeneration of mitochondria. 760 27

Familial amyotrophic lateral sclerosis is a degenerative motor neuron disease associated in some cases with the presence of a mutant form of Cu/Zn superoxide dismutase. We have studied the stability of the gly100-->glu mutant in extracts of red cells obtained from members of a family with a history of the disease. Extracts containing the mutant had an average 68% of normal superoxide dismutase activity. On heating at 65 degrees C, these extracts lost activity at twice the rate of extracts containing only the normal enzyme. Decreased heat stability was also evident on native polyacrylamide gel electrophoresis with activity staining. This showed selective loss of first the mutant homodimer and then the heterodimer of the enzyme. Decreased stability intracellularly could be a factor in motor neuron degeneration.
 ...
PMID:Decreased thermal stability of red blood cell glu100-->gly superoxide dismutase from a family with amyotrophic lateral sclerosis. 763 96

Mutations in the Cu/Zn superoxide dismutase (SOD1) gene are responsible for some cases of familial amyotrophic lateral sclerosis (ALS). We have shown that SOD1 mutations can also occur in apparently sporadic ALS. To establish how often this happens we have undertaken a study of the prevalence of SOD1 mutations in an unselected cohort of Scottish ALS patients, with both sporadic (n = 57) and familial (n = 10) disease. Single strand conformation polymorphism analysis was used to scan for new mutations, and selective restriction enzyme digestion to screen for 11 of the 20 SOD1 mutations published to date. We detected mutations in five (50%) of the familial ALS patients and also in four (7%) of the sporadic patients. One mutation, ile113thr, seems to be particularly prevalent in the Scottish population since it was detected in a total of 6/67 (9%) unrelated cases.
 ...
PMID:Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients. 764 59


1 2 3 4 5 6 7 8 9 10 Next >>