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)

Glutamate-mediated excitotoxicity is implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The astroglial glutamate transporter EAAT2 plays a major role in maintaining low levels of extracellular glutamate in the central nervous system. Multiple EAAT2 mRNA transcripts have been described, but those retaining intron 7 or skipping exon 9 are reported to be specific to the motor cortex, spinal cord, and cerebrospinal fluid of ALS patients. We sought to verify these findings using a TaqMan (Elmer Biosystems, Warrington, UK) real-time reverse transcriptase polymerase chain reaction assay, which provides a sensitive and reliable quantitative measure of EAAT2 transcript copy ratios. We analyzed RNA extracted from frozen postmortem tissue from affected and unaffected central nervous system regions dissected from 17 sporadic ALS patients, 7 Alzheimer's disease patients, and 19 control subjects. We have demonstrated unequivocally that intron 7 retaining and exon 9 skipping variants can be detected in all individuals and in all central nervous system regions studied. The mean ratio of "variant" to "normal" transcripts did not differ significantly between patient and control groups. Although our assay could detect transcript concentrations in cerebrospinal fluid as low as 10 pg/ml, none were detected in 17 ALS and 8 control samples. We conclude that ALS is not associated with elevated levels of EAAT2 transcripts retaining intron 7 and skipping exon 9. An alternative explanation must be sought for the disturbance of glutamate homeostasis reported in ALS.
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PMID:Intron 7 retention and exon 9 skipping EAAT2 mRNA variants are not associated with amyotrophic lateral sclerosis. 1135 55

We studied the role of glutamate excitotoxicity in motor neuron degeneration in the wobbler mouse (wr/wr), a model of amyotrophic lateral sclerosis and spinal muscular atrophies. Choline acetyltransferase (ChAT) activity was decreased in the cervical spinal cord and in the muscles innervated by nerves originating in this region of wobbler mice, but no differences were found in the lumbar spinal cord and in the hindleg muscles. Glial fibrillar acid protein (GFAP), a marker of reactive gliosis, was significantly higher in the cervical spinal cord of wobbler mice aged 4 weeks than in controls and the differences were more marked at 12 weeks; no differences were found in the lumbar spinal cord. In spite of this selective degeneration of motor neurons (resulting in strong decrease in the neuronal glutamate transporter EAAC1) and reactive gliosis in the cervical spinal cord, the levels of the glial glutamate transporter proteins GLT-1 and GLAST were similar in wobbler and control mice. Plasma concentrations of excitatory amino acids were no different at any time examined. Our results exclude the involvement of decrease in glutamate GLT 1 transporter in the motor neuron degeneration in wobbler mice.
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PMID:Glutamate transporters in the spinal cord of the wobbler mouse. 1143 4

Glutamate-induced excitotoxicity is suggested to play a central role in the development of amyotrophic lateral sclerosis (ALS), although it is still unclear whether it represents a primary cause in the cascade leading to motor neurone death. We used western blotting, immunocytochemistry and in situ hybridization to examine the expression of GLT-1 in transgenic mice carrying a mutated (G93A) human copper-zinc superoxide dismutase (TgSOD1 G93A), which closely mimic the features of ALS. We observed a progressive decrease in the immunoreactivity of the glial glutamate transporter (GLT-1) in the ventral, but not in the dorsal, horn of lumbar spinal cord. This effect was specifically found in 14- and 18-week-old mice that had motor function impairment, motor neurone loss and reactive astrocytosis. No changes in GLT-1 were observed at 8 weeks of age, before the appearance of clinical symptoms. Decreases in GLT-1 were accompanied by increased glial fibrillary acidic protein (GFAP) levels and no change in the levels of GLAST, another glial glutamate transporter. The glutamate concentration in the cerebrospinal fluid (CSF) of TgSOD1 G93A mice was not modified at any of the time points examined, compared with age-matched controls. These findings indicate that the loss of GLT-1 protein in ALS mice selectively occurs in the areas affected by neurodegeneration and reactive astrocytosis and it is not associated with increases of glutamate levels in CSF. The lack of changes in GLT-1 at the presymptomatic stage suggests that glial glutamate transporter reduction is not a primary event leading to motor neurone loss.
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PMID:Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels. 1172 66

The mechanisms leading to neurodegeneration in ALS (amyotrophic lateral sclerosis) are not well understood, but cytosolic protein aggregates appear to be common in sporadic and familial ALS as well as transgenic mouse models expressing mutant Cu/Zn superoxide dismutase (SOD1). In this study, we systematically evaluated the presence of these aggregates in three different mouse models (G93A, G85R, and G37R SOD1) and compared these aggregates to those seen in cases of sporadic and familial ALS. Inclusions and loss of motor neurons were observed in spinal cords of all of these three mutant transgenic lines. Since a copper-mediated toxicity hypothesis has been proposed to explain the cytotoxic gain-of-function of mutant SOD1, we sought to determine the involvement of the copper chaperone for SOD1 (CCS) in the formation of protein aggregates. Although all aggregates contained CCS, SOD1 was not uniformly found in the inclusions. Similarly, CCS-positive skein-like inclusions were rarely seen in ALS neurons. These studies do not provide strong evidence for a causal role of CCS in aggregate formation, but they do suggest that protein aggregation is a common event in all animal models of the disease. Selected proteins, such as the glutamate transporter GLT-1, were not typically observed within the inclusions. Most inclusions were positively stained with antibodies recognizing ubiquitin, proteasome, Hsc70 in transgenic lines, and some Hsc70-positive inclusions were detected in sporadic ALS cases. Overall, these observations suggest that inclusions might be sequestered into ubiquitin-proteasome pathway and some chaperone proteins such as Hsc70 may be involved in formation and/or degradation of these inclusions.
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PMID:Histological evidence of protein aggregation in mutant SOD1 transgenic mice and in amyotrophic lateral sclerosis neural tissues. 1174 89

A decrease in expression of the glutamate transporter GLT-1 is thought to be responsible for the increase in extracellular glutamate observed in patients with amyotrophic lateral sclerosis (ALS) and in a transgenic mouse model of ALS. We examined protein levels of the glutamate transporters GLT-1, GLAST and EAAC1 in the G93A (SOD1) transgenic mouse model of ALS. GLT-1 was detected in two bands (72 and 150 kD). Semi-quantitative analysis of Western blots showed that GLT-1 levels in sensorimotor cortex, brain stem, and cervical and lumbar spinal cord of G93A mice did not differ significantly from controls, either at end stage or at 60- or 90-days old. Nevertheless, other differences were found in GLT-1 at end stage. The percentage of total GLT-1 in the 150 kD band increased significantly (p<0.05) in the spinal cord and was elevated in the brain stem and cortex. Furthermore, brain stem and spinal cord GLT-1 from G93A mice showed retarded mobility on gels compared to controls (M(r) approximately equal to 77.3+/-2.3 and 164.3+/-3.1 vs. 72.2+/-2.4 and 153.6+/-4.7, respectively). GLAST and EAAC1 were unchanged in both amount and mobility. These results show that a loss of GLT-1 protein is not necessary for ALS-like neurodegeneration in G93A mice. However, the changes in GLT-1 mobility and distribution indicate that GLT-1 is altered in mice with the SOD1 mutation.
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PMID:GLT-1 glutamate transporter levels are unchanged in mice expressing G93A human mutant SOD1. 1179 Mar 92

Transgenic overexpression of Cu(+2)/Zn(+2) superoxide dismutase 1 (SOD1) harboring an amyotrophic lateral sclerosis (ALS)-linked familial genetic mutation (SOD1(G93A)) in a Sprague-Dawley rat results in ALS-like motor neuron disease. Motor neuron disease in these rats depended on high levels of mutant SOD1 expression, increasing from 8-fold over endogenous SOD1 in the spinal cord of young presymptomatic rats to 16-fold in end-stage animals. Disease onset in these rats was early, approximately 115 days, and disease progression was very rapid thereafter with affected rats reaching end stage on average within 11 days. Pathological abnormalities included vacuoles initially in the lumbar spinal cord and subsequently in more cervical areas, along with inclusion bodies that stained for SOD1, Hsp70, neurofilaments, and ubiquitin. Vacuolization and gliosis were evident before clinical onset of disease and before motor neuron death in the spinal cord and brainstem. Focal loss of the EAAT2 glutamate transporter in the ventral horn of the spinal cord coincided with gliosis, but appeared before motor neuron/axon degeneration. At end-stage disease, gliosis increased and EAAT2 loss in the ventral horn exceeded 90%, suggesting a role for this protein in the events leading to cell death in ALS. These transgenic rats provide a valuable resource to pursue experimentation and therapeutic development, currently difficult or impossible to perform with existing ALS transgenic mice.
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PMID:Focal loss of the glutamate transporter EAAT2 in a transgenic rat model of SOD1 mutant-mediated amyotrophic lateral sclerosis (ALS). 1181 50

Because abnormalities of glutamatergic neurotransmission in psychiatric illness are likely not limited to glutamate receptor expression, we investigated expression of excitatory amino acid transporters (EAATs) in the striatum. The EAATs, normally expressed in both glia (EAAT1 and EAAT2) and neurons (EAAT3 and EAAT4), have previously been implicated in Huntington's disease, amyotrophic lateral sclerosis, and schizophrenia. In this study, we investigated striatal expression of transcripts encoding EAATs in tissue from mood disordered and schizophrenic subjects. With probes designed for the human EAAT1, EAAT2, EAAT3, and EAAT4 transcripts, we performed in situ hybridization and detected decreased expression of EAAT3 and EAAT4 transcripts in the striatum in bipolar disorder. We also detected decreased EAAT3 transcript expression in schizophrenia and decreased EAAT4 transcript expression in major depressive disorder. These results suggest that changes in striatal transporter mRNA expression are restricted to neuronal EAATs and extend the body of evidence implicating abnormal glutamatergic neurotransmission in schizophrenia and mood disorders.
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PMID:Striatal excitatory amino acid transporter transcript expression in schizophrenia, bipolar disorder, and major depressive disorder. 1185 Jan 51

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by a progressive loss of motoneurons and degeneration of motor axons. We show that overexpression of hepatocyte growth factor (HGF) in the nervous system attenuates motoneuron death and axonal degeneration and prolongs the life span of transgenic mice overexpressing mutated Cu2+/Zn2+ superoxide dismutase 1. HGF prevented induction of caspase-1 and inducible nitric oxide synthase (iNOS) in motoneurons and retained the levels of the glial-specific glutamate transporter (excitatory amino acid transporter 2/glutamate transporter 1) in reactive astrocytes. We propose that HGF may be the first example of an endogenous growth factor that can alleviate the symptoms of ALS by direct neurotrophic activities on motoneurons and indirect activities on glial cells, presumably favoring a reduction in glutamatergic neurotoxicity.
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PMID:Overexpression of HGF retards disease progression and prolongs life span in a transgenic mouse model of ALS. 1215 33

Glutamate-mediated neurotoxicity and a reduced expression of the excitatory amino acid transporter 2 (EAAT2) have been described in the pathogenesis of several acute and chronic neurological conditions. EAAT2 is the major carrier of glutamate in the mammalian brain. However, the principles of EAAT2 expression regulation are not fully understood. For the human brain, extensive alternative splicing of the EAAT2 RNA has been shown. To delineate the complex RNA regulation of EAAT2 we investigated whether the murine species is a suitable model for the study of EAAT2 splicing events. We identified five splice variants (mEAAT2/5UT1-5) encoding different 5'-untranslated sequences and two distinct N-termini of the putative EAAT2 polypeptide. In the murine CNS we found a region-specific expression pattern of the novel 5'-variants of EAAT2 as shown by in situ hybridization, dot blotting and competitive reverse transcription polymerase chain reaction. Furthermore, we performed an expression analysis of the EAAT2 splice variants in the spinal cord of a transgenic model (SOD1G93A) of amyotrophic lateral sclerosis, a motor neurone disease for which altered splicing of EAAT2 has been discussed. We found an increased expression of mEAAT2/5UT4 and a reduction of mEAAT2/5UT5 in the early course of the disease. We conclude that alternative splicing of 5'-sequences may contribute to the regional expression of the EAAT2 RNA and was altered in the pre-symptomatic stage of the SOD1G93A-mouse model for amyotrophic lateral sclerosis.
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PMID:Alternative splicing of the 5'-sequences of the mouse EAAT2 glutamate transporter and expression in a transgenic model for amyotrophic lateral sclerosis. 1215 83

Excitotoxicity may play a role in certain disorders of the motor system thought to be caused by environmentally acquired toxins, including lathyrism and domoic acid poisoning. Motor neurons appear to be particularly susceptible to toxicity mediated via alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-kainate receptors. There is a body of evidence implicating glutamatergic toxicity as a contributory factor in the selective neuronal injury occurring in amyotrophic lateral sclerosis (ALS). Interference with glutamate-mediated toxicity is so far the only neuroprotective therapeutic strategy that has shown benefit in terms of slowing disease progression in ALS patients. Biochemical studies have shown decreased glutamate levels in central nervous system (CNS) tissue and increased levels in the cerebrospinal fluid (CSF) of ALS patients. CSF from ALS patients is toxic to neurons in culture, apparently via a mechanism involving AMPA receptor activation. There is evidence for altered expression and function of glial glutamate transporters in ALS, particularly excitatory amino acid transporter 2 (EAAT2). Abnormal splice variants of EAAT2 have been detected in human CNS. Mitochondrial dysfunction may contribute to excitotoxicity in ALS. Induction of neuronal nitric oxide synthase and cyclooxygenase 2 in ALS may also lead to significant interactions with regulation of the glutamate transmitter system. Certain features of motor neurons may predispose them to the neurodegenerative process in ALS, such as the cell size, mitochondrial activity, neurofilament content, and relative lack of certain calcium-binding proteins and molecular chaperones. Motor neurons appear vulnerable to toxicity mediated by calcium-permeable AMPA receptors. The relatively low expression of the glutamate receptor 2 (GluR2) AMPA receptor subunit and the high current density caused by the large number and density of cell surface AMPA receptors are potentially important factors that may predispose to such toxicity.
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PMID:Update on the glutamatergic neurotransmitter system and the role of excitotoxicity in amyotrophic lateral sclerosis. 1236 9

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