Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.36 (caspase-1)
 6,285 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Familial amyotrophic lateral sclerosis (FALS)-linked mutations in copper-zinc superoxide dismutase (SOD1) cause motor neuron death through one or more acquired toxic properties. We analyzed the molecular mechanism underlying motor neuron degeneration in the transgenic mouse model expressing the SOD1 gene with G93A mutation. Using cDNA microarray, the differentially expressed genes were identified in the spinal cords of G93A mice, 30 being elevated and seven decreased. cDNA microarray analysis to monitor gene expression during neurodegeneration revealed an up-regulation of genes related to an inflammatory process, such as the tumor necrosis factor-alpha (TNF-alpha) gene, resulting from glial cell activation, together with the change in apoptosis-related gene expression, such as caspase-1. The increased expression of the inflammation- and apoptosis-related genes occurred at 11 weeks of age in the presymptomatic stage prior to motor neuron death. These results suggest a mechanism of neurodegeneration that includes an inflammatory response as an important component. Thus, ALS has paralleled other neurodegenerative disorders, such as Alzheimer's and prion diseases, in which the inflammatory process is believed to participate directly in neuronal death.
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PMID:Differential expression of inflammation- and apoptosis-related genes in spinal cords of a mutant SOD1 transgenic mouse model of familial amyotrophic lateral sclerosis. 1179 54

Minocycline mediates neuroprotection in experimental models of neurodegeneration. It inhibits the activity of caspase-1, caspase-3, inducible form of nitric oxide synthetase (iNOS) and p38 mitogen-activated protein kinase (MAPK). Although minocycline does not directly inhibit these enzymes, the effects may result from interference with upstream mechanisms resulting in their secondary activation. Because the above-mentioned factors are important in amyotrophic lateral sclerosis (ALS), we tested minocycline in mice with ALS. Here we report that minocycline delays disease onset and extends survival in ALS mice. Given the broad efficacy of minocycline, understanding its mechanisms of action is of great importance. We find that minocycline inhibits mitochondrial permeability-transition-mediated cytochrome c release. Minocycline-mediated inhibition of cytochrome c release is demonstrated in vivo, in cells, and in isolated mitochondria. Understanding the mechanism of action of minocycline will assist in the development and testing of more powerful and effective analogues. Because of the safety record of minocycline, and its ability to penetrate the blood-brain barrier, this drug may be a novel therapy for ALS.
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PMID:Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. 1198 68

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

Mutations in the superoxide dismutase 1 (SOD1) gene cause the degeneration of motor neurons in familial amyotrophic lateral sclerosis (FALS). An apoptotic process including caspase-1 and -3 has been shown to participate in the pathogenesis of FALS transgenic (Tg) mouse model. Here we report that IAP proteins, potent inhibitors of apoptosis, are involved in the FALS Tg mouse pathologic process. The levels of X-linked inhibitor of apoptosis protein (XIAP) mRNA and protein were significantly decreased in the spinal cord of symptomatic G93A-SOD1 Tg mice compared with littermates. In contrast, the levels of cIAP-1 mRNA and protein were increased in symptomatic G93A-SOD1 Tg mice, whereas the levels of cIAP-2 mRNA and protein were unchanged. In situ hybridization showed that the expression of XIAP was remarkably reduced in the motor neurons of Tg mice, and the expression of cIAP-1 was strongly increased in the reactive astrocytes of Tg mice. Overexpression of XIAP markedly inhibited the cell death and caspase-3 activity in the neuro2a cells expressing mutant SOD1. Deletional mutant analysis revealed that the N-terminal domain of XIAP, the BIR1-2 domains, was essential for this inhibitory activity. These results suggest that XIAP plays a role in the apoptotic mechanism in the progression of disease in mutant SOD1 Tg mice and holds therapeutic possibilities for FALS.
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PMID:X-Linked inhibitor of apoptosis protein is involved in mutant SOD1-mediated neuronal degeneration. 1215 81

Transgenic expression of mutant superoxide dismutase-1 (SOD1) produces an animal model of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder. We have previously shown that the mitochondrial-dependent programmed cell death (PCD) pathway, including the redistribution of Bax, the cytosolic release of cytochrome c, and the activation of caspase-9, is recruited during neurodegeneration in spinal cords of transgenic mutant SOD1 mice. Herein, we show that the pro-PCD protein Bid is highly expressed in spinal cords of both wild-type and transgenic mutant SOD1 mice. While full-length Bid is found in the spinal cord of the two groups of mice, its cleaved form is only seen in transgenic mutant SOD1 mice, as early as the beginning of symptoms. In contrast, activated caspase-8, which is known to cleave Bid, is detected only at the end-stage of the disease. We also found that the expression of a dominant negative mutant of caspase-1 attenuates Bid cleavage as well as the mitochondrial release of cytochrome c, and the ensuing activation of caspase-9 and -3 in spinal cords of transgenic mutant SOD1 mice. These findings suggest that Bid cleavage may occur in this model by a pathway other than caspase-8 and shed light onto the molecular correlates of the previously reported beneficial effect of caspase-1 inhibition in transgenic mutant SOD1 mice.
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PMID:Instrumental activation of bid by caspase-1 in a transgenic mouse model of ALS. 1221 39

Amyotrophic lateral sclerosis is characterized by selective motor neuron degeneration. An apoptotic pathway is thought to be involved. It is difficult, however, to analyze the molecular pathogenic mechanism in single motor neurons because of complexity in the neural tissue, which consists of multiple lineages of cells neighboring motor neurons. We quantified the caspase-1 and -3 mRNA in single motor neurons and neighboring glial cells isolated from the spinal ventral horn of mutant SOD1 transgenic (Tg) mice and littermates. Motor neurons and neighboring glial cells were isolated from spinal sections by laser microdissection, and the mRNAs were quantified by RT-PCR. In the Tg mice, caspase-1 mRNA was first upregulated in motor neurons and second in glial cells. The caspase-3 mRNA was increased in motor neurons following the caspase-1 mRNA. These results indicated that caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells of the Tg mice, and that mRNAs in isolated cells can be accurately assessed using our procedures.
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PMID:Caspase-1 and -3 mRNAs are differentially upregulated in motor neurons and glial cells in mutant SOD1 transgenic mouse spinal cord: a study using laser microdissection and real-time RT-PCR. 1271 36

Caspase-11 is a key regulator of caspase-1 and caspase-3 activation under pathological conditions. We show here that the expression of caspase-11 is upregulated in the spinal cord of superoxide dismutase 1 (SOD1) G93A transgenic mice, a mouse model of amyotrophic lateral sclerosis (ALS), before the onset of motor dysfunction and remains at the high levels throughout the course of disease. The caspase-1- and caspase-3-like activities, as well as the level of interleukin-1beta, were significantly reduced in the spinal cord of symptomatic caspase-11-/-;SOD1 G93A mice compared with that of caspase-11+/-; SOD1 G93A mice. However, neurodegeneration, inflammatory responses, and the disease onset and progression in SOD1 G93A transgenic mice were not altered by the ablation of caspase-11 gene. Thus, although caspases may contribute to certain aspects of pathology in this mouse model of ALS, their inhibition is not sufficient to prevent neurodegeneration. Our study urges caution when considering the inhibition of caspases as a direct therapeutic method for the treatment of chronic neurodegenerative diseases.
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PMID:Dissociation between neurodegeneration and caspase-11-mediated activation of caspase-1 and caspase-3 in a mouse model of amyotrophic lateral sclerosis. 1284 44

Mutations in the gene coding for the ubiquitous, anti-oxidant enzyme Cu,Zn superoxide dismutase (SOD1) are associated with familial amyotrophic lateral sclerosis (fALS), a fatal disease characterized by selective loss of motor neurons. Expression of a mutant SOD1 typical of fALS patients restricted to either motor neurons or astrocytes is insufficient to generate a pathological phenotype in mouse models, suggesting that a deleterious interplay between different cell types is necessary for the pathogenesis of the disease. In this study, we demonstrate the actual role of a functional cross-talk between glial and neuronal cells expressing fALS mutant G93A-SOD1, where an increase in the production of reactive oxygen species occurs. We show that human glioblastoma cells expressing G93A-SOD1 induce activation of caspase-1, release of cytokines, and activation of apoptotic pathways in cocultured human neuroblastoma cells also expressing G93A-SOD1. Activation of caspase-1 and caspase-3 is observed also in neuroblastoma lines expressing other fALS-SOD1s (G37R, G85R, and I113T) cocultured with glioblastoma lines expressing the corresponding mutant enzymes. These effects are consequent to activation of inflammatory processes in G93A-glioblastoma cells stimulated by cocultured G93A-neuroblastoma. Furthermore, selective death of embryonal spinal motor neurons from G93A-SOD1 transgenic mice is induced by coculture with G93A-glioblastoma and prevented by inhibition of NO synthase. Proinflammatory cytokines, interferon-gamma, and nitric oxide are among the molecular signals exchanged between glial and neuronal cells that generate a functional interplay between the two cell types. This cross-talk may be crucial for the pathogenesis of SOD1-linked fALS but also for the more common sporadic form of the disease, where markers of increased oxidative stress and of glial activation have been found.
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PMID:Cell death in amyotrophic lateral sclerosis: interplay between neuronal and glial cells. 1520 63

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of brainstem and spinal motoneurons. Although prevention of motoneuronal degeneration has been postulated as the primary target for a cure, accumulating evidence suggests that microglial accumulation contributes to disease progression. This study was designed to assess the ability of HGF to modulate microglial accumulation and motoneuronal degeneration in brainstem motor nuclei, using double transgenic mice overexpressing mutated SOD1(G93A) and HGF (G93A/HGF). Histological and immunohistochemical analyses of the tissues of G93A/HGF mice revealed a marked decrease in the number of microglia and reactive astrocytes and an attenuation of the loss of motoneurons in facial and hypoglossal nuclei compared with G93A mice. HGF overexpression attenuated monocyte chemoattractant protein-1 (MCP-1) induction, predominantly in astrocytes; suppressed activation of caspase-1, -3 and -9; and, increased X chromosome-linked inhibition of apoptosis protein (XIAP) in the motoneurons of G93A mice. The implication is that HGF reduces microglial accumulation by suppressing MCP-1 induction and prevents motoneuronal death through inhibition of pro-apoptotic protein activation. These findings suggest that, in addition to direct neurotrophic activity on motoneurons, HGF-suppression of gliosis may retard disease progression, making HGF a potential therapeutic agent for the treatment of ALS patients.
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PMID:Hepatocyte growth factor (HGF) attenuates gliosis and motoneuronal degeneration in the brainstem motor nuclei of a transgenic mouse model of ALS. 1793 11

The aim of this study was to quantify spinal cord expression of genes known to cause familial amyotrophic lateral sclerosis (FALS) or influence survival in a large cohort of sporadic cases of ALS (SALS), in order to determine their relevance to pathogenic mechanisms occurring in SALS. The expression of superoxide dismutase 1 (SOD1), vesicle associated membrane protein (VAPB), senataxin (SETX), dynactin (DCTN1), vascular endothelial growth factor (VEGF), insulin-like growth factor-1 (IGF1), the small heat shock proteins, HSPB1 and HSPB8, and three genes activated during disease progression, caspases-1 and -3 and glial fibrillary acidic protein (GFAP), were quantified. Robust changes in the expression of four genes were found, VAPB mRNA levels were decreased in the spinal cord of ALS patients compared to controls (p<0.006), whilst HSPB1, HSPB8 and caspase-1 showed significant increases (1.5-2.3-fold). Expression of VAPB mRNA and protein was predominantly localised to large motor neurones further supporting the relevance of this finding to disease progression occurring in SALS.
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PMID:Vesicle associated membrane protein B (VAPB) is decreased in ALS spinal cord. 1870 Nov 94


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