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)

In amyotrophic lateral sclerosis (ALS) it is not known how or why the motor neurons die, but a clue is provided by observations that the dying cells discharge spontaneously, producing muscle fasciculations. The fasciculations can arise either proximally or distally in the motor unit, suggesting a widespread disturbance of membrane excitability. To test for this, we applied the technique of threshold electrotonus to ulnar motor axons at the wrist, comparing the responses to 100 ms polarizing currents in 11 ALS patients with those from 15 normal controls, six patients with benign fasciculations, 19 with lower motor neuron disorders and six with upper motor neuron disorders. We found that the motor axons of ALS patients, unlike those in the neurological control groups, responded abnormally to subthreshold depolarizing currents, becoming either more (seven cases) or much less excitable (four cases) than normal. Both types of abnormality could be reproduced in rat nerves in vitro, and in a computer model of human motor axons, by reducing voltage dependent potassium conductances. When sufficient potassium channels were blocked, the model axon became unstable and depolarized regeneratively, resulting in an abrupt fall in excitability. We conclude that the fasciculations in ALS are caused by an imbalance between functional sodium and potassium channels, and we propose that this ion channel dysfunction could also be responsible for the motor neuron degeneration in this disease.
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PMID:Axonal ion channel dysfunction in amyotrophic lateral sclerosis. 753 98

The medicinal and food use of seed from the cycad plant (Cycas spp.), which contains the neurotoxin cycasin, is a proposed etiological factor for amyotrophic lateral sclerosis/Parkinsonism dementia complex (ALS/PDC), a prototypical neurodegenerative disease found in the western Pacific. Cycasin, the beta-D-glucoside of methylazoxymethanol might enter neurons and other cells via a glucose transporter. Since the intestinal brush-border Na+/glucose cotransporter plays a major role in the absorption of monosaccharides, the following studies were conducted to determine if cycasin, the beta-D-glucoside of methylazoxymethanol, is a substrate for the transporter. We measured the ability of cycasin to (i) inhibit Na+/glucose uptake into rabbit intestinal brush-border membrane vesicles, and (ii) to generate current by the cloned Na+/glucose cotransporter (SGLT1) expressed in Xenopus laevis oocytes. The results show that cycasin inhibits Na(+)-dependent sugar transport in the vesicles, and cycasin generates phlorizin-sensitive currents in oocytes. We conclude that cycasin is a substrate for the intestinal brush-border Na+/glucose cotransporter, albeit with a lower affinity than D-glucose. This suggests that cycasin may be absorbed from the gut lumen by the cotransporter, and as a result either cycasin or the aglycone is presented to the blood-brain barrier for uptake into the brain.
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PMID:Transport of cycasin by the intestinal Na+/glucose cotransporter. 803 85

Neurofibrillary tangles (NFT), one of the neurodegenerative features of Alzheimer's disease, Down's syndrome and normal aging, is a constant, widespread neuropathological finding in Guamanian amyotrophic lateral sclerosis (ALS), parkinsonism-dementia (PD) and in neurologically normal Guamanians, dying of causes other than ALS and PD. NFT in brain tissue sections of patients with Guamanian ALS and PD were immunoreactive to antibodies directed against a 43-amino acid synthetic peptide homologous to amyloid beta/A4-protein (anti-SP43) associated with Alzheimer's disease. NFT extracted from frozen brain tissues of Guamanian patients with ALS and PD and from tissues of neurologically normal Guamanians were congophilic and birefringent. By negative-stain electron microscopy, NFT preparations contained bundles and/or isolated single, straight, unpaired filaments in Guamanian ALS and occasionally pairing of filaments in neurologically normal Guamanians, measuring 5-20 nm in diameter. Formic acid digestion of NFT preparations, followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and size-exclusion high-pressure liquid chromatography, showed a protein with an apparent molecular mass of 4- to 4.5-kDa, which by Western blot analysis was immunoreactive to anti-SP43. Immunoabsorption of purified NFT or SP43 with anti-SP43 abolished immunostaining. Our study corroborate previous data that amyloid beta/A4-protein is present in NFT in Guamanian PD. Furthermore, our data indicate that amyloid beta/A4-protein is present in NFT in brain tissues of patients with Guamanian ALS and in neurologically normal Guamanians, suggesting a common mechanism of amyloidogenesis with NFT formation in Alzheimer's disease and normal brain aging.
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PMID:Neurofibrillary tangles of Guamanian amyotrophic lateral sclerosis, parkinsonism-dementia and neurologically normal Guamanians contain a 4- to 4.5-kilodalton protein which is immunoreactive to anti-amyloid beta/A4-protein antibodies. 821 85

There has been remarkable progress in the identification of mutations in genes that cause inherited neurological disorders. Abnormalities in the genes for Huntington disease, neurofibromatosis types 1 and 2, one form of familial amyotrophic lateral sclerosis, fragile X syndrome, myotonic dystrophy, Kennedy syndrome, Menkes disease, and several forms of retinitis pigmentosa have been elucidated. Rare disorders of neuronal migration such as Kallmann syndrome, Miller-Dieker syndrome, and Norrie disease have been shown to be due to specific gene defects. Several muscle disorders characterized by abnormal membrane excitability have been defined as mutations of the muscle sodium or chloride channels. These advances provide opportunity for accurate molecular diagnosis of at-risk individuals and are the harbinger of new approaches to therapy of these diseases.
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PMID:Molecular genetics in neurology. 791 6

Amyotrophic lateral sclerosis (ALS) is a severe neurological disorder clinically characterized by progressive muscle weakness, amyotrophy, fasciculations and signs of corticospinal tract deficits. The cause is unknown but several hypotheses are currently proposed. In familial forms of ALS, a mutation of the Cu-Zn superoxide dismutase gene was reported in some patients. Autoimmunity and neurofilament dysfunction were also observed. The last hypothesis is linked to excitotoxicity. This cellular phenomenon is associated with the overstimulation of glutamate post-synaptic receptors, leading to neuronal degeneration. Abnormal glutamate metabolism was also discovered in ALS patients. In these conditions, riluzole, a pharmacological agent that reduces glutamate release from nerve terminals, was administered to ALS patients. Riluzole is an anti-convulsant and a neuroprotective agent and specifically blocks sodium channels in their inactivated states. In a recent double blind placebo controlled study, riluzole was given to 77 patients (placebo 78 patients). After 1 year of treatment 58% of the placebo-treated patients were still alive compared to 74% of patients treated with riluzole. The prolonged survival was significant in the overall population and in the bulbar-onset group.
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PMID:Riluzole and ALS therapy. 887 31

Riluzole, a benzothiazole, affects neurons by 3 mechanisms: by inhibiting excitatory amino acid release, inhibiting events following stimulation of excitatory amino acid receptors and stabilising the inactivated state of voltage-dependent sodium channels. It has demonstrated neuroprotective activity in vivo and in vitro. Results from 2 randomised double-blind placebo-controlled trials in patients with amyotrophic lateral sclerosis (ALS; motor neuron disease) have demonstrated that riluzole can extend survival and/or time to tracheostomy. After 18 months, the relative risk of death or tracheostomy with riluzole 100 mg/day was reduced by 21%. Although riluzole slowed the rate of deterioration in muscle strength in the first trial, this was not confirmed in the second, larger trial. Riluzole had no effect on any other functional or secondary variable. Gastrointestinal effects, anorexia, asthenia, circumoral paraesthesia and dizziness were reported more frequently with riluzole than placebo. Elevated alanine aminotransferase levels were observed in 10.6 versus 3.8% of patients treated with riluzole 100 mg/day versus placebo, leading to treatment withdrawal in 3.8 versus 2.1% of patients. In conclusion, riluzole is the first drug that has been shown to have an effect on survival in patients with ALS. Although the effect of riluzole was modest, it has allowed some insight into the pathogenesis of ALS from which future gains may be made.
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PMID:Riluzole. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential in amyotrophic lateral sclerosis. 889 67

The excitotoxic hypothesis of neurodegeneration has stimulated much interest in the possibility of using compounds that will block excitotoxic processes to treat neurologic disorders. Riluzole is a neuroprotective drug that blocks glutamatergic neurotransmission in the CNS. Riluzole inhibits the release of glutamic acid from cultured neurons, from brain slices, and from corticostriatal neurons in vivo. It is thought these effects may be partly due to inactivation of voltage-dependent sodium channels on glutamatergic nerve terminals, as well as activation of a G-protein-dependent signal transduction process. Riluzole also blocks some of the postsynaptic effects of glutamic acid by noncompetitive blockade of N-methyl-D-aspartate (NMDA) receptors. In vivo, riluzole has neuroprotective, anticonvulsant, and sedative properties. In a rodent model of transient global cerebral ischemia, a complete suppression of the ischemia-evoked surge in glutamic acid release has been observed. In vitro, riluzole protects cultured neurons from anoxic damage, from the toxic effects of glutamic-acid-uptake inhibitors, and from the toxic factor in the CSF of patients with amyotrophic lateral sclerosis.
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PMID:The pharmacology and mechanism of action of riluzole. 895 95

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but several observations suggest that glutamate could participate in selective motor neuron degeneration. Extracellular levels of glutamate are elevated in ALS. Synaptic concentrations of glutamate are regulated by high-affinity glutamate transport, and defects in glutamate transport have also been observed in ALS tissue. Three sodium-dependent glutamate transporters have now been identified: a neuronal transporter EAAC1, and two astroglial transporters GLT-1 and GLAST. The defect in glutamate transport in ALS appears to be relatively specific for the GLT-1 subtype. The role of chronic excess glutamate and glutamate transporter loss has been investigated in experimental paradigms, where it was found that excitotoxicity could account for selective motor neuron degeneration. These culture paradigms have demonstrated that motor neurons are sensitive to glutamate toxicity via non-NMDA receptors and that various agents (e.g., antioxidants, glutamate release inhibitors, non-NMDA receptor antagonists) can be neuroprotective. These experimental studies will provide a basis for understanding the primary and secondary role of glutamate in motor neuron death and will provide important insight into possible therapeutic interventions.
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PMID:Excitotoxicity and neurodegeneration in amyotrophic lateral sclerosis. 902 Dec 56

The "glutamate hypothesis" is one of three major pathophysiological mechanisms of motor neurone injury towards which current research effort into amyotrophic lateral sclerosis (ALS) is directed. There is great structural and functional diversity in the glutamate receptor family which results from combinations of 14 known gene products and their splice variants, with or without additional RNA editing. It is possible that motor neurones express a unique molecular profile of glutamate receptors. Abnormal activation of glutamate receptors is one of five main candidates as a final common pathway to neuronal death. In classical acute excitotoxicity, there is influx of Na+ and CI-, and destabilisation of intracellular Ca2+ homeostasis, which activates a cascade of harmful biochemical events. The concept of secondary excitotoxicity, where cellular injury by glutamate is triggered by disturbances in neuronal energy status, may be particularly relevant to a chronic neurodegenerative disease such as ALS. Data are now beginning to emerge on the fine molecular structure of the glutamate receptors present on human motor neurones, which have a distinct profile of AMPA receptors. Two important molecular features of motor neurones have been identified that may contribute to their vulnerability to neurodegeneration. The low expression of calcium binding proteins and the low expression of the GluR2 AMPA receptor subunit by vulnerable motor neurone groups may render them unduly susceptible to calcium-mediated toxic events following glutamate receptor activation. Eight lines of evidence that indicate a disturbance of glutamatergic neurotransmission in ALS patients are reviewed. The links between abnormal activation of glutamate receptors and other potential mechanisms of neuronal injury, including activation of calcium-mediated second messenger systems and free radical mechanisms, are emphasised. Riluzole, which modulates the glutamate neurotransmitter system, has been shown to prolong survival in patients with ALS. Further research may allow the development of subunit-specific therapeutic targeting of glutamate receptors and modulation of "downstream" events within motor neurones, aimed at protecting vulnerable molecular targets in specific populations of ALS patients.
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PMID:Glutamate, excitotoxicity and amyotrophic lateral sclerosis. 917 65

In some families with amyotrophic lateral sclerosis (ALS), the disease is linked to mutations in the gene encoding CuZn-superoxide dismutase. The mutant CuZn-superoxide dismutases appear to cause motor neuron degeneration by a toxic property, suggested to be linked to an altered reactivity of the active-site Cu ions. Asp90Ala mutant CuZn-superoxide dismutase was isolated from six patients with ALS, allowing properties of the mutant enzyme synthesized and conditioned in patients with ALS to be examined. The molecular mass of the Asp90Ala mutant CuZn-superoxide dismutase was 45 Da lower than that of the wild-type enzyme, as expected from the amino acid exchange. The mobility after sodium dodecyl sulfate-polyacrylamide gel electrophoresis was markedly increased, however, suggesting altered properties of the polypeptide. The mutant CuZn-superoxide dismutase showed a minimal reduction in stability but did not differ significantly from the wild-type enzyme in enzymic activity, in content and affinity for active-site Cu ions and in the propensity to catalyze formation of hydroxyl radicals. Our findings suggest that the deleterious effect of mutant CuZn-superoxide dismutases on motor neurons in ALS is not related to altered reactivity of active-site Cu ions, resulting in increased oxidant stress. Attention should therefore also be directed at other mechanisms and properties of the mutant polypeptides and their degradation products.
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PMID:Normal binding and reactivity of copper in mutant superoxide dismutase isolated from amyotrophic lateral sclerosis patients. 923 27


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