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)

The GLT-1 and GLAST astroglial transporters are the glutamate transporters mainly involved in maintaining physiological extracellular glutamate concentrations. Defects in neurotransmitter glutamate transport may represent an important component of glutamate-induced neurodegenerative disorders (such as amyotrophic lateral sclerosis) and CNS insults (ischemia and epilepsy). We characterized the protein expression of GLT-1 and GLAST in primary astrocyte-neuron cocultures derived from rat hippocampal tissues during neuron differentiation/maturation. GLT-1 and GLAST are expressed by morphologically distinct glial fibrillary acidic protein-positive astrocytes, and their expression correlates with the status of neuron differentiation/maturation and activity. Up-regulation of the transporters paralleled the content of the synaptophysin synaptic vesicle marker p38, and down-regulation was a consequence of glutamate-induced neuronal death or the reduction of synaptic activity. Finally, soluble factors in neuronal-conditioned media prevented the down-regulation of the GLT-1 and GLAST proteins. Although other mechanisms may participate in regulating GLT-1 and GLAST in the CNS, our data indicate that soluble factors dependent on neuronal activity play a major regulating role in hippocampal cocultures.
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PMID:The GLT-1 and GLAST glutamate transporters are expressed on morphologically distinct astrocytes and regulated by neuronal activity in primary hippocampal cocultures. 1093 89

Death pathways restricted to specific neuronal classes could potentially allow for precise control of developmental neuronal death and also underlie the selectivity of neuronal loss in neurodegenerative disease. We show that Fas-triggered death of normal embryonic motoneurons requires transcriptional upregulation of neuronal NOS and involves Daxx, ASK1, and p38 together with the classical FADD/caspase-8 cascade. No evidence for involvement of this pathway was found in cells other than motoneurons. Motoneurons from transgenic mice overexpressing ALS-linked SOD1 mutants (G37R, G85R, or G93A) displayed increased susceptibility to activation of this pathway: they were more sensitive to Fas- or NO-triggered cell death but not to trophic deprivation or excitotoxic stimulation. Thus, triggering of a motoneuron-restricted cell death pathway by neighboring cells might contribute to motoneuron loss in ALS.
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PMID:Motoneuron death triggered by a specific pathway downstream of Fas. potentiation by ALS-linked SOD1 mutations. 1235 90

Interferon-inducible, double-stranded RNA-dependent protein kinase PKR is well known as an early cellular responder to viral infection. Activation of PKR has been associated with a number of downstream cell stress and cell death events, including a generalized shutdown of protein translation, activation of caspase-8, participation in JNK and p38 MAPK pathways, activation of NF-kappaB, etc. Recently, the activation of PKR has also been described in several neurodegenerative diseases, including Huntington disease, Alzheimer disease, and amyotrophic lateral sclerosis. Although the relationship between PKR and these diseases is still unclear, the overlap between known functions of PKR and biochemical events that occur in these neuropathologies are discussed here.
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PMID:PKR activation in neurodegenerative disease. 1498 95

Neurofilament middle and heavy chains (NFM and NFH) are heavily phosphorylated on their carboxy-terminal side-arm domains in axons. The mechanisms that regulate this phosphorylation are complex. Here, we demonstrate that p38alpha, a member of the stress-activated protein kinase family, will phosphorylate NFM and NFH on their side-arm domains. Aberrant accumulations of neurofilaments containing phosphorylated NFM and NFH side-arms are a pathological feature of amyotrophic lateral sclerosis (ALS) and we also demonstrate that p38alpha and active forms of p38 family kinases are associated with these accumulations. This is the case for sporadic and familial forms of ALS and also in a transgenic mouse model of ALS caused by expression of mutant superoxide dismutase-1 (SOD1). Thus, p38 kinases may contribute to the aberrant phosphorylation of NFM and NFH side-arms in ALS.
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PMID:p38alpha stress-activated protein kinase phosphorylates neurofilaments and is associated with neurofilament pathology in amyotrophic lateral sclerosis. 1520 59

The identification of the pathogenic mechanism of selective motor neuron (MN) death in amyotrophic lateral sclerosis (ALS) may lead to the development of new therapies to halt or slow the disease course. A novel, MN-specific, Fas-mediated programmed cell death (PCD) pathway has been reported in MNs which involves the activation of p38 MAP kinase (phospho-p38) and neuronal nitric oxide synthase (nNOS). PCD was found to be exacerbated in MNs expressing ALS-linked superoxide dismutase (SOD) mutations. Because this MN-specific pathway was investigated in vitro, we performed an in vivo study to evaluate its potential involvement in MN loss in the lumbar region of spinal cord of mutant SOD transgenic (G93A) mice. Compared to nontransgenic littermates, we found significant increases in the numbers of immunopositive ventral horn MNs of G93A mice as young as 60 days of age for several constituents of this putative PCD pathway, including phospho-p38, nNOS, phospho-ASK1 MAP kinase kinase, and active caspase-3. This study provides in vivo evidence of an MN-specific PCD pathway that may be a pathogenic mechanism of ALS and may be activated very early in the disease process, well before clinical symptoms are evident (200 days). These findings suggest that early diagnosis and therapeutic intervention may be critical for the successful treatment of the disease. These enzymes may provide new markers for earlier diagnosis of ALS and new molecular targets for therapeutic intervention.
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PMID:Activation of programmed cell death markers in ventral horn motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in a transgenic mouse model. 1549 59

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder, characterized by the degeneration of upper and lower motor neurons (MNs). Central nervous system features include a loss of Betz cells and other pyramidal cells from sensorimotor cortex. The intrinsic mechanism underlying this selective motor neuron loss has not been identified. A recent in vitro study has provided evidence of a novel programmed cell death (PCD) pathway that is unique to spinal cord MNs and is exacerbated by superoxide dismutase (SOD) mutations. This PCD pathway is triggered through the Fas receptor and involves the apoptosis signal-regulating kinase 1 (ASK1), the p38 MAP kinase, and the neuronal form of nitric oxide synthase (nNOS). Previously, we found significant increases in the numbers of ventral horn MNs immunopositive for these enzymes in the spinal cords of mutant SOD transgenic (G93A) mice as early as 60 days of age, suggesting that this pathway may be active in vivo. Since the upper MNs of ALS patients and G93A mice are also known to degenerate, the purpose of the present study was to investigate the possible activation of this PCD pathway in the MNs of the sensorimotor cortex of G93A transgenic mice. Compared to non-transgenic littermates, the G93A mice showed significant increases in the numbers of MNs immunopositive for the active (phosphorylated) forms of ASK1, p38, MKK3/6 (the known activator of p38), and also active caspase-3, as early as 60 days of age. Another stress-activated protein kinase, c-Jun N-terminal kinase (JNK), commonly activated in other neurodegenerative disorders such as Alzheimer's disease, showed no increases in G93A mice at any age. These results suggest that, not only has a PCD pathway been activated in the cortical MNs, but one that may be unique to ALS. Moreover, these findings suggest that earlier diagnosis and therapeutic intervention may be possible for successful treatment of ALS. Consequently, these enzymes may provide the biochemical markers to enable earlier diagnosis of ALS and molecular targets for the development of new therapeutic compounds.
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PMID:Activation of the stress-activated MAP kinase, p38, but not JNK in cortical motor neurons during early presymptomatic stages of amyotrophic lateral sclerosis in transgenic mice. 1591 Jul 77

Phosphorylated p38 mitogen-activated protein kinase (p38MAPK), but not activated c-jun-N-terminal kinase (JNK), increases in the motor neurons of transgenic mice overexpressing ALS-linked SOD1 mutants at different stages of the disease. This effect is associated with a selective increase of phosphorylated MKK3-6, MKK4 and ASK1 and a concomitant upregulation of the TNFalpha receptors (TNFR1 and TNFR2), but not IL1beta and Fas receptors. Activation of both p38 MAPK and JNK occurs in the activated microglial cells of SOD1 mutant mice at the advanced stage of the disease; however, this effect is not accompanied by the concomitant activation of the upstream kinases ASK1 and MKK3,4,6, while both the TNFRs are overexpressed in these cells. No changes of the upstream p38MAPK cascade kinases or TNFRs occur in reactive astrocytes. These findings highlight the activation of a selective intracellular signaling pathway in the motor neurons of SOD1 mutant mice, which is likely implicated in their death.
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PMID:Activation of the p38MAPK cascade is associated with upregulation of TNF alpha receptors in the spinal motor neurons of mouse models of familial ALS. 1621 74

The reasons for the cellular specificity and slow progression of motoneuron diseases such as ALS are still poorly understood. We previously described a motoneuron-specific cell death pathway downstream of the Fas death receptor, in which synthesis of nitric oxide (NO) is an obligate step. Motoneurons from ALS model mice expressing mutant SOD1 showed increased susceptibility to exogenous NO as compared with controls. Here, we report a signaling mechanism whereby NO leads to death of mutant, but not control, motoneurons. Unexpectedly, exogenous NO triggers expression of Fas ligand (FasL) in cultured motoneurons. In mutant SOD1(G93A) and SOD1(G85R), but not in control motoneurons, this up-regulation results in activation of Fas, leading through Daxx to phosphorylation of p38 and further NO synthesis. This Fas/NO feedback amplification loop is required for motoneuron death in vitro. In vivo, mutant SOD1(G93A) and SOD1(G85R) mice show increased numbers of positive motoneurons and Daxx nuclear bodies weeks before disease onset. Moreover, FasL up-regulation is reduced in the presence of transgenic dominant-negative Daxx. We propose that chronic low-level activation of the Fas/NO feedback loop may underlie the motoneuron loss that characterizes familial ALS and may help to explain its slowly progressive nature.
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PMID:Chronic activation in presymptomatic amyotrophic lateral sclerosis (ALS) mice of a feedback loop involving Fas, Daxx, and FasL. 1658 1

The pathogenetic processes underlying the selective motor neuron degeneration in amyotrophic lateral sclerosis (ALS) are complex and still not completely understood even in the cases of inherited disease caused by mutations in the Cu/Zn superoxide dismutase-dependent (SOD1) gene. Recent evidence supports the view that ALS is not a cell-autonomous disease and that glial-neuron cross-talk, throughout cytokines and other toxic factors like the nitric oxide and superoxide, is a crucial determinant for the induction of motor neuron death. This cell-cell interaction may determine the progression of the disease through processes that are likely independent of the initial trigger and that may converge on the activation of intracellular death pathways in the motor neurons. In this review we provide support to the hypothesis that aberrant expression and activity of p38 mitogen protein-activated kinases cascade (p38MAPK) in motor neurons and glial cells may play a role in the development and progression of ALS. Increased activation of p38MAPK may phosphorylate neuron-specific substrates altering their physiological properties and it may turn on responsive genes leading to neurotoxicity.
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PMID:Inter- and intracellular signaling in amyotrophic lateral sclerosis: role of p38 mitogen-activated protein kinase. 1690 17

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the selective loss of motor neurons. Stress activated protein kinases (SAPK) have been suggested to play a role in the pathogenesis of ALS. We studied the relevance of p38 MAPK for motor neuron degeneration in the mutant SOD1 mouse. Increased levels of phospho-p38 MAPK were present in the motor neurons and microglia of the ventral spinal cord. The p38 MAPK-inhibitor, SB203580, completely inhibited mutant SOD1-induced apoptosis of motor neurons and blocked LPS-induced activation of microglia. Semapimod, a p38 MAPK inhibitor suitable for clinical use, prolonged survival of mutant SOD1 mice to a limited extent, but largely protected motor neurons and proximal axons from mutant SOD1-induced degeneration. Our data confirm the abnormal activation of p38 MAPK in mutant SOD1 mice and the involvement of p38 MAPK in mutant SOD1-induced motor neuron death. We demonstrate the effect of p38 MAPK inhibition on survival of mutant SOD1 mice and reveal a dissociation between the effect on survival of motor neurons and that on survival of the animal, the latter likely depending on the integrity of the entire motor axon.
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PMID:Inhibition of p38 mitogen activated protein kinase activation and mutant SOD1(G93A)-induced motor neuron death. 1734 81


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