Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pathogenesis of sporadic amyotrophic lateral sclerosis (ALS) is unknown, but defects in synaptosomal high-affinity glutamate transport have been observed. In experimental models, chronic loss of glutamate transport can produce a loss of motor neurons and, therefore, could contribute to the disease. With the recent cloning of three glutamate transporters, i.e., EAAC1, GLT-1, and GLAST, it has become possible to determine if the loss of glutamate transport in ALS is subtype specific. We developed C-terminal, antioligopeptide antibodies that were specific for each glutamate transporter. EAAC1 is selective for neurons, while GLT-1 and GLAST are selective for astroglia. Tissue from various brain regions of ALS patients and controls were examined by immunoblot or immunocytochemical methods for each transporter subtype. All tissue was matched for age and postmortem delay. GLT-1 immunoreactive protein was severely decreased in ALS, both in motor cortex (71% decrease compared with control) and in spinal cord. In approximately a quarter of the ALS motor cortex specimens, the loss of GLT-1 protein (90% decrease from control) was dramatic. By contrast, there was only a modest loss (20% decrease from control) of immunoreactive protein EAAC1 in ALS motor cortex, and there was no appreciable change in GLAST. The minor loss of EAAC1 could be secondary to loss of cortical motor neurons. As a comparison, glial fibrillary acidic protein, which is selectively localized to astroglia, was not changed in ALS motor cortex. Because there is no loss of astroglia in ALS, the dramatic abnormalities in GLT-1 could reflect a primary defect in GLT-1 protein, a secondary loss due to down regulation, or other toxic processes.
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PMID:Selective loss of glial glutamate transporter GLT-1 in amyotrophic lateral sclerosis. 761 29

Studies of the coding region of the neuronal glutamate transporter of 6 amyotrophic lateral sclerosis (ALS) patients and 10 controls show an identical pattern of four reported amino acid variations. No mutations and polymorphisms were detected in 5 sporadic ALS patients and a single patient with the familial form of the disease.
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PMID:Studies of the coding region of the neuronal glutamate transporter gene in amyotrophic lateral sclerosis. 777 58

The distribution and density of glutamate transporter sites was determined in human cervical and lumbar spinal cord, by quantitative autoradiography using [3H]D-aspartate. In the normal human spinal cord (n = 8) there was specific binding of [3H]D-aspartate throughout the spinal grey matter, with the highest levels observed in the substantia gelatinosa and central grey matter. In the ventral horns, particularly at the L5 level, focal hot spots of binding were observed in a distribution corresponding to that of lower motor neuron somata. Comparison of motor neuron disease (MND) cases (n = 12) with normal controls showed a reduction in the density of [3H]D-aspartate binding in the intermediate grey matter and the substantia gelatinosa of the lumbar cord. These changes were more marked in the amyotrophic lateral sclerosis (ALS) compared to the progressive muscular atrophy (PMA) subgroup, and may be due to loss of glutamatergic terminals of the corticospinal tract. The changes observed in the cervical cord were milder and did not reach statistical significance. No differences were found between [3H]D-aspartate binding in the spinal cords of the normal controls and a neurological disease control group (n = 6), suggesting that the changes observed in MND are disease specific. These findings provide further evidence in support of a disturbance of glutamatergic neurotransmission in MND.
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PMID:[3H]D-aspartate binding sites in the normal human spinal cord and changes in motor neuron disease: a quantitative autoradiographic study. 781 73

High affinity glutamate transporters regulate levels of extracellular glutamate in the central nervous system. Impaired glutamate transport has been implicated in the pathogenesis of amyotrophic lateral sclerosis (ALS). The glutamate transporter subtypes GluT-1 and EAAC1 have previously been mapped to human chromosomes 5p13 and 9p24, respectively. In the present study, the GLT-1 subtype was mapped to human chromosome 11p11.2-p13 by fluorescence in situ hybridization. The possible clinical implications of this finding are discussed.
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PMID:Localization of the gene encoding the human L-glutamate transporter (GLT-1) to 11p11.2-p13 by fluorescence in situ hybridization. 878 89

Here, we report a mutation screening by single-stranded conformational analysis of the astroglial human brain glutamate transporter (HBGT) II complementary DNA in patients with amyotrophic lateral sclerosis. The conformational analysis data indicate a lack of sequence variations in the HBGT II coding region in 6 patients with amyotrophic lateral sclerosis and the same number of nonneurological control subjects. In both groups, three variants of the HBGT II 5' untranslated region were isolated. We have no evidence that the reported complementary DNA variants are disease specific.
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PMID:The glial glutamate transporter complementary DNA in patients with amyotrophic lateral sclerosis. 879 37

Previous studies have suggested that defective high-affinity glutamate uptake, due mainly to a major loss of the astroglial-specific GLT-1 glutamate transporter, underlies the selective motoneuron degeneration observed in sporadic ALS (24, 28). If a defect in glutamate transport underlies the pathogenesis of sporadic ALS, the glutamate transporter subtype found to be lost in sporadic ALS should be present in abundance in the affected motor nuclei under normal conditions. To investigate this, we used immunohistochemical methods to analyze the localization of two subtypes of high-affinity glutamate transporters in the cranial motor nuclei of normal monkey brain stem: GLT-1, localized to astroglia; and EAAC1, localized to neurons. Our results indicated that all motor cell groups of monkey brain stem are rich in the GLT-1 glutamate transporter, which is localized to astroglial cells and processes that surround and envelop motoneuron cell bodies and dendrites. Image analysis indicated that the abundance of GLT-1 immunoreactive astroglial elements in ALS-vulnerable motor cell groups (i.e., the trigeminal, facial, and hypoglossal motor cell groups) is higher than in ALS-resistant motor cell groups (i.e., the oculomotor, trochlear, and abducens motor cell groups), and statistical analysis showed that this difference is significant. Our results also indicated that both ALS-vulnerable and ALS-resistant motor cell groups of monkey brain stem are relatively poor in EAAC1 immunoreactivity. Therefore, in the case of a loss in the GLT-1 glutamate transporter in sporadic ALS, glutamate may increase in the vicinity of motoneurons in all brain-stem motor cell groups, but especially in the ALS-vulnerable motor cell groups, which are normally richer in GLT-1. Increased extracellular glutamate could lead to excess entry of Ca2+ into motoneurons via glutamate-gated or voltage-activated Ca2+ channels and produce degeneration of those motoneurons unable to resist the insult. Since motoneurons in the ALS-resistant motor cell groups of the brain stem are enriched in the Ca2+ buffering protein parvalbumin, they should be better able to resist the damage than the majority of motoneurons in the ALS-vulnerable motor cell groups, which lack parvalbumin (20).
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PMID:Differential abundance of glutamate transporter subtypes in amyotrophic lateral sclerosis (ALS)-vulnerable versus ALS-resistant brain stem motor cell groups. 893 60

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

High levels of familial Amyotrophic Lateral Sclerosis (ALS)-linked SOD1 mutants G93A and G37R were previously shown to mediate disease in mice through an acquired toxic property. We report here that even low levels of another mutant, G85R, cause motor neuron disease characterized by an extremely rapid clinical progression, without changes in SOD1 activity. Initial indicators of disease are astrocytic inclusions that stain intensely with SOD1 antibodies and ubiquitin and SOD1-containing aggregates in motor neurons, features common with some cases of SOD1 mutant-mediated ALS. Astrocytic inclusions escalate markedly as disease progresses, concomitant with a decrease in the glial glutamate transporter (GLT-1). Thus, the G85R SOD1 mutant mediates direct damage to astrocytes, which may promote the nearly synchronous degeneration of motor neurons.
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PMID:ALS-linked SOD1 mutant G85R mediates damage to astrocytes and promotes rapidly progressive disease with SOD1-containing inclusions. 905 2

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

The human glutamate transporter EAAT2 (GLT-1) is of major importance for synaptic glutamate reuptake, and reportedly, a candidate gene for neurodegenerative diseases such as amyotrophic lateral sclerosis, Alzheimer's disease and epilepsy. Here we report the polymerase chain reaction (PCR) cloning of two novel EAAT2 transcripts, named EAAT2-C1 and EAAT2-C2, which originate from alternative splicing of the human EAAT2 gene. EAAT2-C1 results from skipping of the protein coding exon eight. In contrast, EAAT2-C2 is characterized by usage of internal splice sites in the exons five and six. The splicing events lead to a deletion of 45 and 107 amino acids, respectively, located in the C-terminal and central part of the putative protein.
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PMID:Alternative splicing of the glutamate transporter EAAT2 (GLT-1). 950 18


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