UMLS:C0002736 - FACTA Search

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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transplantation of hNT Neurons derived from the human teratocarcinoma cell-line (NTera2/D1) has been shown to ameliorate motor dysfunction in a number of injury or disease models in which the deficits are fairly localized. However, these cells have not been used before in a model with more extensive neurodegeneration. The aim of this study is to determine the effects of hNT Neuron transplants on motor neuron function in a mouse model of familial amyotrophic lateral sclerosis (FALS) in which there is a substitution of Alanine for Glycine at position 93 of the human SOD1 gene (G93A). Amyotrophic lateral sclerosis is a fatal degenerative motor neuron disease affecting the spinal cord, brainstem, and cortex. This disease clinically manifests as progressive muscular weakness and atrophy, leading to paralysis and death within 3-5 years of diagnosis. The FALS represents 10-13% of all cases. A range of behavioral tests was used to examine spontaneous locomotor activity, coordination, and muscle strength of mice. Long-term (10-11 weeks) transplantation of hNT Neurons into the L(4)-L(5) segments of the ventral horn spinal cord of FALS(G93A) mice at 7 weeks of age (before onset of overt behavioral symptoms of disease) delayed the onset of motor dysfunction for at least 3 weeks. The average lifespan of the transplanted mice was 128 days compared to 106 days for media-injected group. The last mouse in the hNT Neuron transplanted group was euthanized at 135 days of age when it display partial paralysis of the hindlimbs. Immunohistochemical analysis of the implanted spinal cords demonstrated the survival of grafted hNT Neurons and showed many healthy-appearing motor neurons near the implant site. These results suggest that hNT Neuron transplantation may be a promising therapeutic strategy for ALS.
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PMID:Positive effect of transplantation of hNT neurons (NTera 2/D1 cell-line) in a model of familial amyotrophic lateral sclerosis. 1192 59

Acetolactate synthase (ALS; EC 4.1.3.18) inhibition is the primary mechanism of action of imazethapyr (IM). However, the precise mechanisms that links ALS inhibition with plant death have not been elucidated. Supply of IM to pea (Pisum sativum L) plants produced an immediate cessation of growth, caused a 50% inhibition of the in vivo ALS activity within 1 day of treatment, and a remarkable accumulation (2.7-times) of free amino acids after 3 days. Carbohydrates (soluble and starch) were accumulated in both leaves and roots. Accumulation of soluble sugars in roots preceded that of starch in leaves, suggesting that the accumulation of carbohydrates in leaves is not the reason for the arrested root growth. A transient pyruvate accumulation was observed in roots, 1 day after the onset of IM supply. This was coincident with an increase in pyruvate decarboxylase (EC 4.1.1.1), and later increases in alcohol dehydrogenase (EC 1.1.1.1), lactate dehydrogenase (EC 1.1.1.27), and alanine amino transferase (EC 2.6.1.2) activities. This enhancement of fermentative activities was coincident with a slight decrease in aerobic respiration. The overall data suggest that the impairment of ALS activity may lead to a fermentative metabolism that may be involved in growth inhibition and plant death.
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PMID:Imazethapyr, an inhibitor of the branched-chain amino acid biosynthesis, induces aerobic fermentation in pea plants. 1197 25

Familial amyotrophic lateral sclerosis (FALS) is often caused by gain-of-function mutations in Cu,Zn-superoxide dismutase (SOD1). Multiprobe ribonuclease protection assays (RPAs) were used to investigate expression of 36 different cytokines and apoptosis-related genes in spinal cords of mice that ubiquitously express human SOD1 bearing a glycine (r) alanine substitution at residue 93 (G93A-SOD1). Mice were studied at late presymptomatic stage (80 days), and at 120 days when the animals experience severe hindlimb paralysis and accumulation of oxidatively modified proteins. Spinal cord tissue from G93A-SOD1 mice expressed a selective subset of macrophage-typical cytokines (monokines) including interleukin (IL)1alpha, IL1beta and IL1RA at 80 days increasing by 120 days. Contrastingly, T-cell derived cytokines (lymphokines) including IL2, IL3 and IL4 were detected at low levels in non-transgenic mice but these were not elevated in G93A-SOD1 mice even at 120 days. Apoptosis-related genes were generally unaffected at 80 days but multiple caspases and death receptor components were up-regulated at 120 days; the only exceptions being FADD and the tumor necrosis factor (TNF)alpha receptor p55 which was up-regulated at 80 days and increased further at 120 days. These data indicate that in the G93A-SOD1 mouse: (i) cytokine expression changes precede bulk protein oxidation and apoptosis gene expression; (ii) lymphocyte contributions to cytokine expression in FALS are likely minor; and (iii) TNFalpha and its receptors may link inflammation to apoptosis in ALS.
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PMID:Temporal patterns of cytokine and apoptosis-related gene expression in spinal cords of the G93A-SOD1 mouse model of amyotrophic lateral sclerosis. 1212 37

Seeds of the Guam cycad Cycas micronesica K.D. Hill (Cycadaceae), which contain ss-methylamino-L-alanine (BMAA), have been implicated in the etiology of the devastating neurodisease ALS-PDC that is found among the native Chamorros on Guam. The disease also occurs in the native populations on Irian Jaya and the Kii Peninsula of Japan, and in all three areas the cycad seeds are used either dietarily or medically. ALS-PDC is a complex of amyotrophic lateral sclerosis and parkinsonism dementia complex with additional symptoms of Alzheimer's. It is well known that Ca(2+) elevations in brain cells can lead to cell death and neurodiseases. Therefore, we evaluated the ability of the cycad toxin BMAA to elevate the intracellular calcium concentration ([Ca(2+)](i)) in dissociated newborn rat brain cells loaded with fura-2 dye. BMAA produced an increase in intracellular calcium levels in a concentration-dependent manner. The increases were dependent not only on extracellular calcium concentrations, but also significantly on the presence of bicarbonate ion. Increasing concentrations of sodium bicarbonate resulted in a potentiation of the BMAA-induced [Ca(2+)](i) elevation. The bicarbonate dependence did not result from the increased sodium concentration or alkalinization of the buffer. Our results support the hypothesis that the neurotoxicity of BMAA is due to an excitotoxic mechanism, involving elevated intracellular calcium levels and bicarbonate. Furthermore, since BMAA alone produced no increase in Ca(2+) levels, these results suggest the involvement of a product of BMAA and CO(2), namely a beta-carbamate, which has a structure similar to other excitatory amino acids (EAA) such as glutamate; thus, the causative agent for ALS-PDC on Guam and elsewhere may be the beta-carbamate of BMAA. These findings support the theory that some forms of other neurodiseases may also involve environmental toxins.
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PMID:The cycad neurotoxic amino acid, beta-N-methylamino-L-alanine (BMAA), elevates intracellular calcium levels in dissociated rat brain cells. 1224 91

The release of [(3)H]D-aspartate ([(3)H]D-ASP) or [(3)H]GABA evoked by glycine from spinal cord synaptosomes was compared in mice expressing mutant human SOD1 with a Gly(93) Ala substitution ([SOD1-G93A(+)]), a transgenic model of amyotrophic lateral sclerosis, and in control mice. Mice expressing mutated SOD1 were killed at the advanced phase of the pathology, when they showed signs of ingestion disability, because of paralysis of the posterior limbs. In control mice glycine concentration-dependently evoked [(3)H]D-ASP and [(3)H]GABA release. Potentiation of the spontaneous release of both amino acids is likely to be mediated by activation of a glycine transporter, since the effects of glycine were counteracted by the glycine transporter blocker glycyldodecylamide but not by the glycine receptor antagonists strychnine and 5,7-dichlorokynurenate. The glycine-evoked release of [(3)H]D-ASP, but not that of [(3)H]GABA, was significantly more pronounced in SOD1-G93A(+) than in control animals.
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PMID:Activation of a glycine transporter on spinal cord neurons causes enhanced glutamate release in a mouse model of amyotrophic lateral sclerosis. 1268 56

Apart from the extensive loss of motor neurons, degeneration of midbrain dopaminergic cells has been described in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). Mice overexpressing the mutant human Cu/Zn superoxide dismutase (SOD1) show an ALS-like phenotype in that they show a progressive death of motor neurons accompanied by degeneration of dopaminergic cells. To describe the functional alterations specifically associated with this dopaminergic dysfunction, we have investigated the corticostriatal synaptic plasticity in mice overexpressing the human SOD1 (SOD1+) and the mutated (Gly(93)-->Ala) form (G93A+) of the same enzyme. We show that repetitive stimulation of the corticostriatal pathway generates long-term depression (LTD) in SOD1+ mice and in control (G93A-/SOD1-) animals, whereas in G93A+ mice the same stimulation generates an N-methyl-D-aspartic acid receptor-dependent long-term potentiation. No significant alterations were found in the intrinsic membrane properties of striatal medium spiny neurons and basal corticostriatal synaptic transmission of G93A+ mice. Bath perfusion of dopamine or the D(2) dopamine receptor agonist quinpirole restored LTD in G93A+ mice. Consistent with these in vitro results, habituation of locomotor activity and striatal-dependent active avoidance learning were impaired in G93A+ mice. Thus, degeneration of dopaminergic neurons in the substantia nigra of G93A+ mice causes substantial modifications in striatal synaptic plasticity and related behaviors, and may be a cellular substrate of the extrapyramidal motor and cognitive disorders observed in familial and sporadic ALS.
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PMID:Altered long-term corticostriatal synaptic plasticity in transgenic mice overexpressing human CU/ZN superoxide dismutase (GLY(93)-->ALA) mutation. 1269 76

The Aspartate-90-Alanine (D90A) mutation on SOD-1 gene, the only known change causing recessive familial amyotrophic lateral sclerosis (FALS), is associated with a uniform phenotype characterized by slowly ascending paresis and long survival. Originally reported in Scandinavian cases, it has also been detected in patients from other countries. A common haplotype, probably of Scandinavian origin, has been demonstrated in D90A recessive pedigrees. In this study we screened the SOD-1 gene for the D90A mutation in 56 Italian patients from north-west Tuscany with sporadic ALS in order to evaluate the occurrence of this mutation and its genotype-phenotype correlation in Italy. We found the homozygous D90A mutation in one patient (1.8%), harboring the classical phenotype related to this mutation. No other mutations were detected in any of the five SOD-1 exons in our group. Our results confirm that recessive D90A mutation is present in Italy and it is associated with the phenotype already described A screening for that mutation, easily made by RFLP, should be made in sporadic ALS patients, especially where clinical investigation indicates its presence.
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PMID:A screening for superoxide dismutase-1 D90A mutation in Italian patients with sporadic amyotrophic lateral sclerosis. 1271 May 11

We recently demonstrated that tumor necrosis factor alpha activates caspase 6, which in turn cleaves transcription factor AP-2 alpha. We mapped the cleavage site at 19 amino acids from the N-terminus at the sequence aspartate-argenine-histidine-aspartate (DRHD). Mutating aspartic acid at position 19 abrogated the cleavage site. From these observations, we hypothesized that the DRHD peptide could act as a caspase 6 inhibitor. To test this hypothesis, the peptide zAsp(Ome)-Arg-His-Asp(Ome)-fluoromethyl ketone (zDRHDfmk) was synthesized. Here we show that zDRHDfmk inhibits TNFalpha-induced caspase 6 activity and apoptosis in breast cancer cells. When compared to other caspase inhibitors, zDRHDfmk inhibited caspase 6 activity more effectively than the general caspase inhibitor zVal-Ala-Lys(Ome)-fluoromethy ketone (zVADfmk) or the caspase 6 inhibitor zVal-Glu-Ile-Asp-(Ome)-fluoromethyl ketone (zVEIDfmk). However, it was less effective in inhibiting TNFalpha-induced apoptosis than zVADfmk or zVEIDfmk, presumably because caspase 6 is only one of at least three effector caspases, the others being caspase 3 and 7, that are active during caspase-dependent apoptosis. The discovery of this sequence-based caspase 6 inhibitor provides a new tool for studying caspase 6. More importantly, it could be used, in combination with other agents, as a drug to inhibit apoptosis in neurodegenrative diseases such as Alzheimer's, Parkinson and amyotrophic lateral sclerosis.
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PMID:Sequence-based discovery of a synthetic peptide inhibitor of caspase 6. 1281 80

Previous investigations showed an impairment of amino acids (AA) metabolism in amyotrophic lateral sclerosis (ALS). It was hypothesized that excitatory AA may play an important role in the etiopathogenesis of this disease. The aim of the study was to determine plasma AA concentrations in ALS patients, and to examine the relationship between AA and the clinical state of ALS patients, the type of ALS onset and the duration of the disease. The study involved 20 ALS patients and 30 control group people. The AA analysis was performed by ion - exchange chromatography on an automatic AA analyser. The results showed significantly decreased concentrations of valine, isoleucine, leucine, tyrosine and aspartate in the plasma of the whole group of ALS patients compared to the control group, and a significantly decreased concentration of arginine in the patients with a long duration of ALS compared to the patients with a short duration. The clinical state of ALS patients significantly influenced only plasma alanine concentration. Other plasma AA concentrations were not significantly associated with clinical parameters of the disease. Our study confirms that metabolic abnormalities concerning AA exist in ALS patients. However, the normal plasma glutamate concentration observed in this study in the whole group of ALS patients compared to the controls does not exclude that this excitatory AA may play a role in neurodegeneration in ALS.
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PMID:Plasma amino acids concentration in amyotrophic lateral sclerosis patients. 1283 61

Heat shock protein 70 (Hsp70) protects cultured motor neurons from the toxic effects of mutations in Cu/Zn-superoxide dismutase (SOD-1), which is responsible for a familial form of the disease, amyotrophic lateral sclerosis (ALS). Here, the endogenous heat shock response of motor neurons was investigated to determine whether a high threshold for activating this protective mechanism contributes to their vulnerability to stresses associated with ALS. When heat shocked, cultured motor neurons failed to express Hsp70 or transactivate a green fluorescent protein reporter gene driven by the Hsp70 promoter, although Hsp70 was induced in glial cells. No increase in Hsp70 occurred in motor neurons after exposure to excitotoxic glutamate or expression of mutant SOD-1 with a glycine--> alanine substitution at residue 93 (G93A), nor was Hsp70 increased in spinal cords of G93A SOD-1 transgenic mice or sporadic or familial ALS patients. In contrast, strong Hsp70 induction occurred in motor neurons with expression of a constitutively active form of heat shock transcription factor (HSF)-1 or when proteasome activity was sufficiently inhibited to induce accumulation of an alternative transcription factor HSF2. These results indicate that the high threshold for induction of the stress response in motor neurons stems from an impaired ability to activate the main heat shock-stress sensor, HSF1.
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PMID:High threshold for induction of the stress response in motor neurons is associated with failure to activate HSF1. 1284 83

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