Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P42574 (caspase-3)
 45,978 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

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

The glial glutamate transporter EAAT2 is primarily responsible for clearance of glutamate from the synaptic cleft and loss of EAAT2 has been previously reported in amyotrophic lateral sclerosis (ALS) and Alzheimer's disease. The loss of functional EAAT2 could lead to the accumulation of extracellular glutamate, resulting in cell death known as excitotoxicity. However, it is still unknown whether it is a primary cause in the cascade leading to neuron degeneration or a secondary event to cell death. The goals of this study were to generate transgenic mice overexpressing EAAT2 and then to cross these mice with the ALS-associated mutant SOD1(G93A) mice to investigate whether supplementation of the loss of EAAT2 would delay or rescue the disease progression. We show that the amount of EAAT2 protein and the associated Na+-dependent glutamate uptake was increased about 2-fold in our EAAT2 transgenic mice. The transgenic EAAT2 protein was properly localized to the cell surface on the plasma membrane. Increased EAAT2 expression protects neurons from L-glutamate induced cytotoxicity and cell death in vitro. Furthermore, our EAAT2/G93A double transgenic mice showed a statistically significant (14 days) delay in grip strength decline but not in the onset of paralysis, body weight decline or life span when compared with G93A littermates. Moreover, a delay in the loss of motor neurons and their axonal morphologies as well as other events including caspase-3 activation and SOD1 aggregation were also observed. These results suggest that the loss of EAAT2 may contribute to, but does not cause, motor neuron degeneration in ALS.
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PMID:Increased expression of the glial glutamate transporter EAAT2 modulates excitotoxicity and delays the onset but not the outcome of ALS in mice. 1291 61

Re-expression of the death-signalling p75 neurotrophin receptor (p75NTR) is associated with injury and neurodegeneration in the adult nervous system. The induction of p75NTR expression in mature degenerating spinal motor neurons of humans and transgenic mice with amyotrophic lateral sclerosis (ALS) suggests a role of p75NTR in the progression of motor neuron disease (MND). In this study, we designed, synthesized and evaluated novel antisense peptide nucleic acid (PNA) constructs targeting p75NTR as a potential gene knockdown therapeutic strategy for ALS. An 11-mer antisense PNA directed at the initiation codon, but not downstream gene sequences, dose-dependently inhibited p75NTR expression and death-signalling by nerve growth factor (NGF) in Schwann cell cultures. Antisense phosphorothioate oligonucleotide (PS-ODN) sequences used for comparison failed to confer such inhibitory activity. Systemic intraperitoneal administration of this antisense PNA to mutant superoxide dismutase 1 (SOD1G93A) transgenic mice significantly delayed locomotor impairment and mortality compared with mice injected with nonsense or scrambled PNA sequences. Reductions in p75NTR expression and subsequent caspase-3 activation in spinal cords were consistent with increased survival in antisense PNA-treated mice. The uptake of fluorescent-labelled antisense PNA in the nervous system of transgenic mice was also confirmed. This study suggests that p75NTR may be a promising antisense target in the treatment of ALS.
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PMID:Antisense peptide nucleic acid-mediated knockdown of the p75 neurotrophin receptor delays motor neuron disease in mutant SOD1 transgenic mice. 1453 57

Mutant copper/zinc superoxide dismutase (SOD1)-overexpressing transgenic mice, a mouse model for familial amyotrophic lateral sclerosis (ALS), provides an excellent resource for developing novel therapies for ALS. Several observations suggest that mitochondria-dependent apoptotic signaling, including caspase-9 activation, may play an important role in mutant SOD1-related neurodegeneration. To elucidate the role of caspase-9 in ALS, we examined the effects of an inhibitor of X chromosome-linked inhibitor of apoptosis (XIAP), a mammalian inhibitor of caspase-3, -7 and -9, and p35, a baculoviral broad caspase inhibitor that does not inhibit caspase-9. When expressed in spinal motor neurons of mutant SOD1 mice using transgenic techniques, XIAP attenuated disease progression without delaying onset. In contrast, p35 delayed onset without slowing disease progression. Moreover, caspase-9 was activated in spinal motor neurons of human ALS subjects. These data strongly suggest that caspase-9 plays a crucial role in disease progression of ALS and constitutes a promising therapeutic target.
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PMID:The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. 1465 37

The significance of copper/zinc superoxide dismutase (SOD1) and neuronal nitric oxide synthase (nNOS) co-localization to neurofilamentous (NF) aggregates in amyotrophic lateral sclerosis (ALS) is unknown. In this study, we have used dissociated motor neurons from either C57BL/6 or mice that over-express the human low molecular weight neurofilament protein (hNFL+/+) to examine the relationship between NF aggregate formation, SOD1 and nNOS co-localization, and the regulation of NMDA-mediated calcium influx in vitro. The intracellular distribution of NF aggregates, SOD1 and nNOS was examined by confocal microscopy and NMDA-induced alterations in intracellular calcium levels using either Oregon green fluorescence or FURA-2 photometric imaging. Cell death was assessed using an antibody to activated caspase-3. C57 Bl/6 motor neurons expressed nNOS in a punctate manner, whereas SOD1 was distributed homogeneously throughout the cytosol. In contrast, hNFL+/+ motor neurons demonstrated co-localization of SOD1 and nNOS by day 9 post-plating, preceding the formation of NF aggregates. Both proteins co-localized to NF aggregates once formed. With NMDA stimulation, aggregate-bearing hNFL+/+ motor neurons demonstrated significant increases in intracellular calcium, whereas only a minimal alteration in intracellular calcium was observed in C57 Bl/6 neurons. Following stimulation with 100 microM NMDA, 75.5+/-5.5% of hNFL+/+ neurons became apoptotic, whereas only 16.3+/-5.3% of C57 Bl/6 were. These observations suggest that the presence of NF aggregates results in a failure of regulation of NMDA-mediated calcium influx, and that this occurs due to the sequestration of nNOS to the NF aggregate, preventing its down-regulation of the NMDA receptor.
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PMID:Sequestration of nNOS in neurofilamentous aggregate bearing neurons in vitro leads to enhanced NMDA-mediated calcium influx. 1503 15

Insulin-like growth factor I (IGF-I) is currently in clinical trials for treatment of amyotrophic lateral sclerosis (ALS), but little is known about how it promotes the survival of motor neurons. In the current study, we examined IGF-I-mediated neuroprotection in an in vitro model of ALS utilizing enriched cultures of embryonic rat spinal cord motor neurons. IGF-I binds to the IGF-I receptor (IGF-IR) in motor neurons and activates MAPK and the downstream effector of phosphatidylinositol 3-kinase (PI-3K) signaling, Akt. IGF-I:IGF-IR signaling involves phosphorylation of IRS-1 and Shc, but not IRS-2. Glutamate, which is elevated in the cerebrospinal fluid of ALS patients, induced DNA fragmentation and caspase-3 cleavage in the spinal cord motor neurons. These effects of glutamate were blocked by co-treatment with IGF-I. However, a delay of IGF-I treatment for as little as 30 min eliminated its neuroprotective effect. Finally, alone, neither the MAPK pathway inhibitor PD98059 nor the PI-3K inhibitor LY294002 blocked the neuroprotective effect of IGF-I, but both inhibitors together were effective in this regard. These results suggest that the dose and timing of IGF-I administration are critical for producing a neuroprotective effect, and also suggest that both the MAPK and PI-3K/Akt pathways can promote the survival of motor neurons. We discuss our results in terms of novel strategies for ALS therapy.
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PMID:IGF-I prevents glutamate-induced motor neuron programmed cell death. 1519 97

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

Creatine mediates remarkable neuroprotection in experimental models of amyotrophic lateral sclerosis, Huntington's disease, Parkinson's disease, and traumatic brain injury. Because caspase-mediated pathways are shared functional mechanistic components in these diseases, as well as in ischemia, we evaluated the effect of creatine supplementation on an experimental stroke model. Oral creatine administration resulted in a remarkable reduction in ischemic brain infarction and neuroprotection after cerebral ischemia in mice. Postischemic caspase-3 activation and cytochrome c release were significantly reduced in creatine-treated mice. Creatine administration buffered ischemia-mediated cerebral ATP depletion. These data provide the first direct correlation between the preservation of bioenergetic cellular status and the inhibition of activation of caspase cell-death pathways in vivo. An alternative explanation to our findings is that creatine is neuroprotective through other mechanisms that are independent of mitochondrial cell-death pathways, and therefore postischemic ATP preservation is the result of tissue sparing. Given its safety record, creatine might be considered as a novel therapeutic agent for inhibition of ischemic brain injury in humans. Prophylactic creatine supplementation, similar to what is recommended for an agent such as aspirin, may be considered for patients in high stroke-risk categories.
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PMID:Prophylactic creatine administration mediates neuroprotection in cerebral ischemia in mice. 1522 38

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by loss of motoneurons in the spinal cord and brain stem. We have characterized motoneuron death in transgenic mice carrying the mutant human copper/zinc superoxide dismutase, as a model for familial ALS. Previous studies have shown the involvement of mitochondria in nerve cell demise in these animals. We report here an early cleavage of caspase-12, residing in the endoplasmic reticulum (ER), in the spinal cord during the course of the disease. Apart from caspase-12, caspase-9, and caspase-3 were activated in the transgenic ALS mice. Staining with an antibody for nitrotyrosine, as a marker for oxidative stress, showed a large increase in the ALS mice. The results indicate that oxidative and ER induced stress causing caspase-12 activation are involved in neuronal death and disease progression in ALS. Caspase-12 and the ER pathway for cell death may constitute potential novel targets for the treatment of ALS.
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PMID:Caspase-12 cleavage and increased oxidative stress during motoneuron degeneration in transgenic mouse model of ALS. 1531 3


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