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)

Familial amyotrophic lateral sclerosis (FALS) has been linked in some families to dominant mutations of the SOD1 gene encoding Cu,Zn superoxide dismutase (Cu,ZnSOD). We have used a transgenic model of FALS based on expression of mutant human Cu,ZnSOD to explore the etiology and therapy of the genetic disease. Expression of mutant, but not wild-type, human Cu,ZnSOD in mice places the brain and spinal cord under oxidative stress. This causes depletion of vitamin E, rather than the typical age-dependent increase in vitamin E content as occurs in nontransgenic mice and in mice expressing wild-type human Cu,ZnSOD. Dietary supplementation with vitamin E delays onset of clinical disease and slows progression in the transgenic model but does not prolong survival. In contrast, two putative inhibitors of the glutamatergic system, riluzole and gabapentin, prolong survival. However, riluzole did not delay disease onset. Thus, there was clear separation of effects on onset, progression, and survival by the three therapeutics tested. This suggests the hypothesis that oxidative damage produced by the expression of mutant Cu,ZnSOD causes slow or weak excitotoxicity that can be inhibited in part by alerting glutamate release or biosynthesis presynaptically.
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PMID:Benefit of vitamin E, riluzole, and gabapentin in a transgenic model of familial amyotrophic lateral sclerosis. 896 44

The data from the literature regarding the presence of a neurotoxic factor in amyotrophic lateral sclerosis (ALS) plasma or cerebrospinal fluid (CSF) remain controversial. As a new approach to this question, we have studied the effect of CSF from ALS patients on the temporal dynamics of the intracellular free calcium concentration ([Ca2+]i) of murine cortical neurons in cultures using Fura-2 fluorescence videomicroscopy and single-cell imaging. CSF from seven ALS patients and controls was added at dilutions up to 20% to cortical neuronal cultures. The in vitro inhibition of CSF on [3H]kainic acid binding showed that the CSF did not contain any substances other than glutamate itself in larger amounts. At the concentrations used, the CSF did not have any effect on [Ca2+]i or on the neuronal responsiveness as defined by the ability of the cells to respond with a transient increase in [Ca2+]i to depolarization induced by KCl. The disturbance of the intracellular calcium homeostasis is one of the key mechanisms of action of excitotoxic compounds mediating delayed neuronal cell death by stimulation of glutamate receptor subtypes. In this study, CSF from ALS patients did not induce immediate rises in [Ca2+]i or disturbances of the intracellular calcium homeostasis when measured over a period of 2 h.
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PMID:Cerebrospinal fluid from amyotrophic lateral sclerosis has no effect on intracellular free calcium in cultured cortical neurons. 897 92

Amyotrophic lateral sclerosis is a progressive degenerative disease of upper and lower motor neurons with a prevalence of 4.3/100.000. The clinical symptoms include peripheral weakness and central spastic paresis and bulbar paralysis (weakness of mimic muscles, atrophy of the tongue, dysarthria). The prognosis leads to death within a few years. Pathogenetic factors are free O2-radicals, a disturbance of glutamate-metabolism, abnormal accumulation of neuronal proteins and autoimmunological mechanisms.
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PMID:[Clinical aspects of amyotrophic lateral sclerosis]. 901 7

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

All mutations in the human gene for CuZn superoxide dismutase (CuZnSOD) reported to date are associated with the disease amyotrophic lateral sclerosis (ALS). These mutations, mostly of a familial nature (ALS 1, MIM 105400), span all of the coding region of this enzyme except for a highly conserved centrally located domain that includes all of exon III. We describe the identification and characterization of two mutations in this region, both found in mice. One mutation, a glutamate to lysine amino acid substitution was found in position 77 (E77K) of the strain SOD1/Ei distributed by the Jackson Laboratory. The other mutation, a lysine to glutamate substitution at position 70 (K70E) of a human transgene, was discovered in mouse line TgHS/SF-155. Enzyme activity measurements and heterodimer analysis of the CuZn SOD variant in SOD1/Ei suggest a mild loss of activity, which differs from the enzyme activity losses detected in patients with autosomal dominant ALS 1. Similarly, the presence of the mutant transgene in TgHS/SF 155 does not produce any phenotypic manifestations.
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PMID:Novel mutations in an otherwise strictly conserved domain of CuZn superoxide dismutase. 906 9

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal illness characterized by upper and lower motor neuron degeneration of adults. Recently, many advances are being made in our understanding of the pathogenesis of ALS, which are the role of autoimmunity, the glutamate excitotoxicity, the neurotrophic factor and the defined mutation of superoxide dismutase in familial ALS cases. The therapeutic trials have been carried out more commonly based on the putative pathogenesis described. Among them, riluzole, antiglutamate agent, is proved to have the survival advantage in a controlled double-blind randomized study. These current putative pathogenesis and therapeutic trials of ALS are discussed.
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PMID:[Amyotrophic lateral sclerosis]. 908 59

We have clinically and electromyographically examined, during a follow-up study, weakened muscles and still clinically normal muscles of 9 patients affected by amyotrophic lateral sclerosis (ALS) and of 3 patients affected by focal benign amyotrophy (FBA). MRC scores corrected with positive semiquantitative evaluations of the number of giant motor unit (MU) action potentials and with negative evaluations of the number of fasciculations and fibrillations potentials have been found to linearly correlate with the percentage of the residual MUs calculated from the mean amplitude and the spike number during maximal voluntary contraction. A main finding is that the loss of MUs slows down in the last 10 months of the disease. It follows that after a phase when the pathological process was accelerated by the toxic effect due to the abnormally high concentration of glutamate released by dead motoneurons, the residual cells because of the decreased motoneuronal density are less exposed to the possible neurotoxic damage.
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PMID:[Effect of motor neuron density on the curve of motor neuron impoverishment in amyotrophic lateral sclerosis]. 910 60

Glutamate transporters play an important role in keeping extracellular glutamate concentrations below the neurotoxic levels. We cloned a human glutamate transporter hGluT-1. In ischemic states, glutamate efflux via glutamate transporters and the extracellular glutamate concentrations are rapidly increased. These phenomenon enlarges the area of neuronal cell death. We showed that L-CCG-III, IV and glutamate block the reverse uptake (efflux) of glutamate in the hGluT-1 expressing HeLa cells. In amyotrophic lateral sclerosis, a glutamate transporter GLT1 was decreased. Decrease of the glutamate transporter will cause the elevation of extracellular glutamate concentrations and will lead to the neuronal injury. Bromocriptine enhances glutamate uptake 1.5 times than in its absence in the hGluT-1 expressing HeLa cells. Enhancing the removal of extracellular glutamate may produce similar effect as those achieved by glutamate-receptor antagonists. At two neuronal death conditions, we showed new possibilities of preventing neuronal cell death by the glutamate transporter regulators.
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PMID:[Glutamate transporter and neuronal cell death]. 912 91

To reconcile the autoimmune and excitotoxic hypotheses regarding the etiology of amyotrophic lateral sclerosis (ALS), we injected rats intraperitoneally with ALS immunoglobulins and monitored CSF glutamate, aspartate, glutamine, and glutathione. CSF glutamate was significantly increased at 24 and 72 hours compared with both basal levels and disease control injected rats. CSF aspartate was increased at 72 hours. Glutamine and glutathione were unchanged. These data suggest that ALS immunoglobulins may enhance CSF glutamate and aspartate levels and contribute to motoneuron injury.
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PMID:Increased CSF glutamate following injection of ALS immunoglobulins. 915 55

Amyotrophic lateral sclerosis is a fatal neurodegenerative disease in which upper and lower motoneurons progressively deteriorate and die. Neuronal damage is most evident in the lower central nervous system, and death generally occurs following central respiratory failure. Proposed and demonstrated mechanisms for amyotrophic lateral sclerosis are diverse, and include altered superoxide dismutase and neurofilament proteins, autoimmune attack, and hyperglutamatergic activity. However, they do not account for the late onset of the disease, its earlier onset in males, and the differential vulnerability of neurons located in the brainstem and spinal cord. It is proposed here that, within the context of a specific defect such as altered superoxide dismutase, age-dependent decline in ascorbate availability triggers the disease. A role for ascorbate, which is found in millimolar levels in neurons, is suggested by a number of consistencies: 1) superoxide radicals being a common substrate for superoxide dismutase and ascorbate; 2) a close association between central nervous system ascorbate levels and injury tolerance; 3) a steady decline in ascorbate plasma levels and cellular availability with age; 4) plasma ascorbate levels being lower in males; 5) an association of ascorbate release with motor activity in central nervous system regions, in vivo; 6) the coupling of brain-cell ascorbate release with glutamate uptake; 7) possible roles for ascorbate modulation of N-methyl-D-aspartate receptor activity; 9) the ability of ascorbate to prevent peroxynitrite anion formation; and 10) evidence supporting the scorbutic guinea pig as a model for amyotrophic lateral sclerosis. Emphasis is placed on the probable competition between superoxide dismutase and ascorbate within the context of a primary defect of metal-binding or metal access in high-concentration proteins such as superoxide dismutase and human heavy neurofilaments. Finally, distinct features of alpha-motoneuronal physiology suggest that cell physiological characteristics such as high metabolic activity and extensive calcium dynamics may render neurons differentially vulnerable in amyotrophic lateral sclerosis.
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PMID:Ascorbate availability and neurodegeneration in amyotrophic lateral sclerosis. 916 Feb 82


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