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)

Embryonic human spinal cord cells have been grown in dissociated monolayer cultures for 1 to 7 weeks. Using cell type specific markers, it was possible to show that the cultures contain neurons, astrocytes and fibroblasts. Electrical membrane properties were studied with patch electrodes using the whole cell recording technique. Neurons had short duration action potentials that could be blocked by tetrodotoxin. The membrane currents in these neurons were studied in voltage clamp experiments. Three types of voltage-dependent currents were observed: a sodium current; a potassium current made up of two components, IA and IK; and a calcium current. Both cholinergic and GABAergic neurons are present in the cultures. There is more choline acetyltransferase activity in cultures prepared from the anterior as compared to the posterior part of the spinal cord, suggesting that the cultures contain motoneurons. This tissue culture preparation was developed for the study of amyotrophic lateral sclerosis; we have been unable to detect the presence of any toxic agent from the serum of these patients on the cultured cells. Experiments are in progress to purify the motoneurons using Percoll gradients.
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PMID:Characterization of dissociated monolayer cultures of human spinal cord. 271 16

Previous studies in our laboratory had demonstrated alterations in the physical state of membrane proteins in erythrocytes in Huntington's disease. In order to assess the specificity of our findings, the results of electron spin resonance studies of protein and lipid components, scanning electron-microscopic studies, enzymatic analyses of membrane-bound sodium plus potassium stimulated, magnesium-dependent adenosine triphosphatase and protein kinase, and cell deformability studies of erythrocyte membranes have been performed in the neurological disorders, Huntington's disease, Friedreich's ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, and myotonic and Duchenne muscular dystrophy. Comparison of the results revealed that alterations in the biophysical and biochemical states of erythrocyte membranes in each disorder are specific to the particular disease state with the exception of those in Friedreich's ataxia and Alzheimer's disease. In the latter instance, the clinical and pathological alterations suggest that these two diseases have different primary defects. Our studies suggest that the molecular basis of each disease is different. In addition, the results suggest that biophysical and biochemical investigations of extraneural tissue in Huntington's disease and other neurological disordes have the potential of clarifying the molecular mechanisms by which these diseases arise.
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PMID:Specificity of biophysical and biochemical alterations in erythrocyte membranes in neurological disorders--Huntington's disease, Friedreich's ataxia, Alzheimer's disease, amyotrophic lateral sclerosis, and myotonic and duchenne muscular dystrophy. 625 Nov 75

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 slow potassium channel blocker 3,4-diaminopyridine (DAP) enhances acetylcholine release from the nerve terminal and improves conduction in unmyelinated nerve. In this open label pilot study, we examined the effect of DAP combined with inpatient rehabilitation in seven patients with motor weakness due to amyotrophic lateral sclerosis (ALS). A single daily 20 mg oral dose of DAP was gradually increased to the maximum tolerated dose, and serum DAP concentrations were measured. Videotaped motor examination (for subsequent "blinded" review and assignment of a quantitative motor score), Functional Independence Measure (FIM) assessment, nerve conduction studies and neuropsychological evaluations were performed on admission, 1 h after maximum DAP dose, and post-treatment. DAP was tolerated in all patients, though dose was limited by gastrointestinal side effects in five patients. The mean peak serum level was 128 (+/- 50) ng/ml, occurring 1.0 (+/- 0.50) h after dose. A modest but statistically significant (p = 0.045) peak in motor score occurred on DAP. A significant (p = 0.045) improvement from baseline in FIM performance was apparent with DAP. Nerve conduction studies showed small increases in evoked response amplitudes and conduction velocities on DAP, but they did not reach statistical significance. No cognitive or affective changes were apparent. This unblinded pilot study shows that DAP is tolerated in ALS patients, and may be associated with functional and electrophysiologic improvement.
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PMID:3,4-diaminopyridine as a treatment for amyotrophic lateral sclerosis. 775 39

Plant amino acids beta-N-oxalylamino-L-alanine (L-BOAA, present in Lathyrus sativus) and beta-N-methylamino-L-alanine (L-BMAA, present in Cycas circinalis) have been implicated in the pathogenesis of human neurological disorders lathyrism and amyotrophic lateral sclerosis-Parkinson's dementia complex of Guam (ALS-PD), respectively. In view of the conflicting reports that have emerged on the role of L-BMAA in ALS-PD, we reinvestigated the comparative toxicity of L-BMAA and L-BOAA. We report here the potent toxicity of L-BOAA as examined in an in vitro model consisting of sagittal slices of mouse brain. Incubation of sagittal slices of mouse brain with L-BOAA (1 pM) resulted in significant leakage of lactate dehydrogenase (LDH) and potassium from the slices into the medium. Under similar conditions, L-BMAA-induced LDH leakage from the slices into the medium was observed only at very high concentration of the toxin, namely 1 mM. N-Methyl-D-aspartate (NMDA) receptor antagonists ameliorated the toxic effects of L-BMAA, while non-NMDA receptor antagonists (quinoxalinediones) protected against the toxicity of L-BOAA. Incubation of slices with L-BOAA for 1 h resulted in extensive vacuolation and degeneration of neurons in the thalamus and brain stem, and to a lesser extent in the hippocampus and cerebellar nuclei. The large sized neurons appeared to be affected to a greater extent than the smaller ones. The neurons in other areas of the brain also revealed variable degree of degeneration with swelling of axons and dendrites.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Billion-fold difference in the toxic potencies of two excitatory plant amino acids, L-BOAA and L-BMAA: biochemical and morphological studies using mouse brain slices. 790 22

Functional abnormalities, especially the excitability changes of axon in the peripheral nerve involvement, were reviewed. In GBS and CIDP, the correlation between conduction block and anti-ganglioside antibodies have been discussed. Using anti GM1 antibody positive sera, the suppression of voltage-gated sodium channels (VGSC) has been reported. Although this findings have not been confirmed, the involvement of VGSC may be an important mechanism for eliciting conduction block. In Isaacs' syndrome, voltage-gated potassium channels (VGKC) were suppressed by autoantibodies to VGKC. Furthermore, in generalized myokymia syndrome which shows only myokymia and muscle cramp without grip myotonia, VGKCs are also suppressed in some cases. These findings suggest that some patients with myokymia and neuromyotonia are induced by anti-VGKC antibodies. For evaluating the axonal excitability in vivo, the threshold electrotonus method have been developed and applied for the involvement of peripheral nerves. In ALS, impairment of potassium conductance was shown and was speculated to have the possible rrelation with fasciculation. Thus threshold electrotonus method will be an important method for evaluating axonal excitability in human. The accumulated knowledge about the involvement of axonal ion channels will expand and will be categorized as axonal channelopathies.
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PMID:[Impairment of peripheral nerve excitability]. 957 60

The defect of neuromuscular transmission is one of the important signs in ALS. The amplitude of a single motor unit potential from patients with ALS often decrease during tonic voluntary contraction. This phenomenon is closely correlated with fatigue seen in the patient. Overfunctioning of Ach release in the nerve terminal might cause the failure of neuromuscular transmission in ALS. Fasciculations is an another characteristic sign and considered mainly to be peripheral axons in origin. It is postulated that the dysfunction of potassium channel in ALS axons makes the hyperexcitability of the axon membrane, causing fasciculations. Magnetic cortical stimulation sometimes evokes the same potentials as fasciculations, implying the hyperexcitability might be present also in spinal motoneurons or even in pyramidal neurons in ALS. All of these findings lead to the hypothesis that hyperexcitability or overactivity of central and peripheral motoneurons is an essential feature in ALS.
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PMID:[Abnormal hyperexcitability in ALS]. 1037 5

High level contamination by natural and industrial sources of the alkali earth metal, barium (Ba) has been identified in the ecosystems/workplaces that are associated with high incidence clustering of multiple sclerosis (MS) and other neurodegenerative diseases such as the transmissible spongiform encephalopathies (TSEs) and amyotrophic lateral sclerosis (ALS). Analyses of ecosystems supporting the most renowned MS clusters in Saskatchewan, Sardinia, Massachusetts, Colorado, Guam, NE Scotland demonstrated consistently elevated levels of Ba in soils (mean: 1428 ppm) and vegetation (mean: 74 ppm) in relation to mean levels of 345 and 19 ppm recorded in MS-free regions adjoining. The high levels of Ba stemmed from local quarrying for Ba ores and/or use of Ba in paper/foundry/welding/textile/oil and gas well related industries, as well as from the use of Ba as an atmospheric aerosol spray for enhancing/refracting the signalling of radio/radar waves along military jet flight paths, missile test ranges, etc. It is proposed that chronic contamination of the biosystem with the reactive types of Ba salts can initiate the pathogenesis of MS; due to the conjugation of Ba with free sulphate, which subsequently deprives the endogenous sulphated proteoglycan molecules (heparan sulfates) of their sulphate co partner, thereby disrupting synthesis of S-proteoglycans and their crucial role in the fibroblast growth factor (FGF) signalling which induces oligodendrocyte progenitors to maintain the growth and structural integrity of the myelin sheath. Loss of S-proteoglycan activity explains other key facets of MS pathogenesis; such as the aggregation of platelets and the proliferation of superoxide generated oxidative stress. Ba intoxications disturb the sodium-potassium ion pump--another key feature of the MS profile. The co-clustering of various neurodegenerative diseases in these Ba-contaminated ecosystems suggests that the pathogenesis of all of these diseases could pivot upon a common disruption of the sulphated proteoglycan-growth factor mediated signalling systems. Individual genetics dictates which specific disease emerges at the end of the day.
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PMID:Chronic barium intoxication disrupts sulphated proteoglycan synthesis: a hypothesis for the origins of multiple sclerosis. 1508

Cu/Zn superoxide dismutase (SOD) mutations are involved in about 20% of all cases of familial amyotrophic lateral sclerosis (FALS). Recently, it has been proposed that aberrant copper activity may be occurring within SOD at an alternative binding, and cysteine 111 has been identified as a potential copper ligand. Using a commercial source of human SOD isolated from erythrocytes, an anomalous absorbance at 325 nm was identified. This unusual property, which does not compromise SOD activity, had previously been shown to be consistent with a sulfhydryl modification at a cysteine residue. Here, we utilized limited trypsin proteolysis and mass spectrometry to show that the modification has a mass of 32 daltons and is located at cysteine 111. The reaction of SOD with sodium sulfide, which can react with cysteine to form a persulfide group, and with potassium cyanide, which can selectively remove persulfide bonds, confirmed the addition of a persulfide group at cysteine 111. Gel electrophoresis and glutaraldehyde cross-linking revealed that this modification makes the acid-induced denaturation of SOD fully irreversible. Furthermore, the modified protein exhibits a slower acid-induced unfolding, and is more resistant to oxidation-induced aggregation caused by copper and hydrogen peroxide. Thus, these results suggest that cysteine 111 can have a biochemical and biophysical impact on SOD, and suggest that it can interact with copper, potentially mediating the copper-induced oxidative damage of SOD. It will be of interest to study the role of cysteine 111 in the oxidative damage and aggregation of toxic SOD mutants.
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PMID:Modification of cysteine 111 in Cu/Zn superoxide dismutase results in altered spectroscopic and biophysical properties. 1509 37

Serum and glucocorticoid-regulated kinase 1 (sgk1) belongs to a family of serine/threonine kinases that is under acute transcriptional control by serum and glucocorticoids. An expanding set of receptors and cellular stress pathways has been shown to enhance sgk1 expression, which is implicated in the regulation of ion channel conductance, cell volume, cell cycle progression, and apoptosis. Recent evidence for the involvement of sgk1 in the early pathogenesis of MPTP-induced Parkinson's disease (PD) prompted us to investigate in more detail its expression and role in animal models of different neurodegenerative diseases. Here, we show that transcription of sgk1 is increased in several animal models of PD and a transgenic model of amyotrophic lateral sclerosis (ALS). The upregulation of sgk1 strongly correlates with the occurrence of cell death. Furthermore, we provide evidence that the Forkhead transcription factor FKHRL1 and some of the voltage-gated potassium channels are physiological substrates of sgk1 in vivo. Using a small interfering RNA approach to silence sgk1 transcripts in vitro, we give evidence that sgk1 exerts a protective role in oxidative stress situations. These findings underline a key role for sgk1 in the molecular pathway of cell death, in which sgk1 seems to exert a protective role.
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PMID:Sgk1, a cell survival response in neurodegenerative diseases. 1612 69


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