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)

Apoptosis has recently been recognized as a mode of cell death in Huntington disease (HD). Apopain, a human counterpart of the nematode cysteine protease death-gene product, CED-3, has a key role in proteolytic events leading to apoptosis. Here we show that apoptotic extracts and apopain itself specifically cleave the HD gene product, huntingtin. The rate of cleavage increases with the length of the huntingtin polyglutamine tract, providing an explanation for the gain-of-function associated with CAG expansion. Our results show that huntingtin is cleaved by cysteine proteases and suggest that HD might be a disorder of inappropriate apoptosis.
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PMID:Cleavage of huntingtin by apopain, a proapoptotic cysteine protease, is modulated by the polyglutamine tract. 869 24

It is unclear how polyglutamine expansion is associated with the pathogenesis of Huntington disease (HD). Here, we provide evidence that polyglutamine expansion leads to the formation of large intracellular aggregates in vitro and in vivo. In vitro these huntingtin-containing aggregates disrupt normal cellular architecture and increase in frequency with polyglutamine length. Huntingtin truncated at nucleotide 1955, close to the caspase-3 cleavage site, forms perinuclear aggregates more readily than full-length huntingtin and increases the susceptibility of cells to death following apoptotic stimuli. Further truncation of huntingtin to nucleotide 436 results in both intranuclear and perinuclear aggregates. For a given protein size, increasing polyglutamine length is associated with increased cellular toxicity. Asymptomatic transgenic mice expressing full-length huntingtin with 138 polyglutamines form exclusively perinuclear aggregates in neurons. These data support the hypothesis that proteolytic cleavage of mutant huntingtin leads to the development of aggregates which compromise cell viability, and that their localization is influenced by protein length.
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PMID:Length of huntingtin and its polyglutamine tract influences localization and frequency of intracellular aggregates. 946 44

To gain insight into the pathogenic mechanisms of Huntington's disease (HD), we have developed a stable cellular model, using a neuroblastoma cell line in which the expression of full-length or truncated forms of wild-type and mutant huntingtin can be induced. While the wild-type forms have the expected cytoplasmic localization, the expression of mutant proteins leads to the formation of cytoplasmic and nuclear inclusions in a time- and polyglutamine length-dependent manner. The inclusions are ubiquitinated, appear more rapidly in cells expressing truncated forms of mutant huntingtin and are correlated with enhanced apoptosis. In lines expressing mutant full-length huntingtin, major characteristics present in Huntington's patients could be modelled. Selective processing of the mutant, but not the wild-type, full-length huntingtin was observed at late time points, with appearance of a breakdown product corresponding to a predicted caspase-3 cleavage product. A more truncated N-terminal fragment of huntingtin is also produced, that appears involved in building up cytoplasmic inclusions at early time points, and later on also nuclear inclusions. This fits with the finding that inclusions in the brain of HD patients are detected only using antibodies directed against epitopes very close to the polyglutamine stretch. This unique model should thus be useful to study the processing mechanism of mutant huntingtin, its role in the formation of intracellular aggregates and the effect of the latter on cellular physiology.
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PMID:A cellular model that recapitulates major pathogenic steps of Huntington's disease. 970 Jan 87

To date, eight neurodegenerative disorders, including Huntington's disease and dentatorubral-pallidoluysian atrophy, have been identified to be caused by expansion of a CAG repeat coding for a polyglutamine (polyQ) stretch. It is, however, unclear how polyQ expansion mediates neuronal cell death observed in these disorders. Here, we have established a tetracycline-regulated expression system producing 19 and 56 repeats of glutamine fused with green fluorescent protein. Induced expression of the 56 polyQ, but not of the 19 polyQ stretch caused marked nuclear aggregation and apoptotic morphological changes of the nucleus. In vitro enzyme assays and Western blotting showed that polyQ56 expression sequentially activated initiator and effector caspases, such as caspase-8 or -9, and caspase-3, respectively. Furthermore, using cell-permeable fluorogenic substrate, the activation of caspase-3-like proteases was demonstrated in intact cells with aggregated polyQ. This is the first direct evidence that the expression of extended polyQ activates caspases and together with the previous findings that some of the products of genes responsible for CAG repeat diseases are substrates of caspase-3 indicates an important role of caspases in the pathogenesis of these diseases.
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PMID:Expression of extended polyglutamine sequentially activates initiator and effector caspases. 1020 51

We review recent advances regarding the pathogenesis of Huntington's disease (HD). This genetic neurodegenerative disorder is caused by an expanded CAG repeat in a gene coding for a protein, with unknown function, called huntingtin. There is selective death of striatal and cortical neurons. Both in patients and a transgenic mouse model of the disease, neuronal intranuclear inclusions, immunoreactive for huntingtin and ubiquitin, develop. Huntingtin interacts with the proteins GAPDH, HAP-1, HIP1, HIP2, and calmodulin, and a mutant huntingtin is specifically cleaved by the proapoptotic enzyme caspase 3. The pathogenetic mechanism is not known, but it is presumed that there is a toxic gain of function of the mutant huntingtin. Circumstantial evidence suggests that excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis play a role.
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PMID:Recent advances on the pathogenesis of Huntington's disease. 1022 5

Huntington disease (HD) is a genetically dominant condition caused by expanded CAG repeats coding for glutamine in the HD gene product huntingtin. Although HD symptoms reflect preferential neuronal death in specific brain regions, huntingtin is expressed in almost all tissues, so abnormalities outside the brain might be expected. Although involvement of nuclei and mitochondria in HD pathophysiology has been suggested, specific intracellular defects that might elicit cell death have been unclear. Mitochondria dysfunction is reported in HD brains; mitochondria are organelles that regulates apoptotic cell death. We now report that lymphoblasts derived from HD patients showed increased stress-induced apoptotic cell death associated with caspase-3 activation. When subjected to stress, HD lymphoblasts also manifested a considerable increase in mitochondrial depolarization correlated with increased glutamine repeats.
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PMID:Increased apoptosis of Huntington disease lymphoblasts associated with repeat length-dependent mitochondrial depolarization. 1050 25

The excitotoxic response of striatal neurons to NMDA and non-NMDA receptor agonists involves the nuclear translocation of transcription factor nuclear factor-kappa B (NF-kappaB) due to IkappaB-alpha degradation. Resultant augmentation in c-Myc, p53 and cyclin D1 expression presages the apoptotic-like destruction of these cells in vivo. To differentiate molecular events triggered by intrastriatally injected quinolinic acid (QA, 60 nmol) and kainic acid (KA, 2.5 nmol), we compared the effects of a caspase-3 inhibitor (DEVD.CHO, 8 microgram intrastriatally), a free radical scavenger (OPC-14117; 600 mg/kg, orally) and ethanol (2.14-8.6 micromol, intrastriatally or 25-100 mmol/kg, orally) on changes induced by these glutamatergic agonists on NF-kappaB cascade components and the apoptotic death of rat striatal neurons in vivo. The results indicated that the QA-induced degradation of IkappaB-alpha is almost totally mediated by a caspase-3-dependent mechanism, while KA-induced IkappaB-alpha degradation is only partially dependent on caspase-3. OPC-14117 attenuated the effects of QA but not KA on IkappaB-alpha degradation, suggesting that oxidative stress contributes to the QA- but not the KA-induced degradation of IkappaB-alpha. In contrast, ethanol inhibited the KA- but not the QA-induced degradation of IkappaB-alpha and the ensuing DNA fragmentation and loss of striatal GABAergic neurons. It would now appear that NF-kappaB activation in striatal neurons induced by NMDA or KA receptor stimulation involves different biochemical mechanisms. Since excitotoxicity associated with NF-kappaB activation may contribute to neuronal degenerative disorders such as Huntington's disease, a more detailed understanding of biochemical events underlying ionotrophic glutamate receptor-stimulated cell death may assist in the discovery of alternative approaches to interdicting the deleterious consequences of excitotoxic insult.
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PMID:NMDA and non-NMDA receptor-stimulated IkappaB-alpha degradation: differential effects of the caspase-3 inhibitor DEVD.CHO, ethanol and free radical scavenger OPC-14117. 1071 66

Huntington's disease is a neurodegenerative disorder caused by CAG expansion that results in expansion of a polyglutamine tract at the extreme N terminus of huntingtin (htt). htt with polyglutamine expansion is proapoptotic in different cell types. Here, we show that caspase inhibitors diminish the toxicity of htt. Additionally, we define htt itself as an important caspase substrate by generating a site-directed htt mutant that is resistant to caspase-3 cleavage at positions 513 and 530 and to caspase-6 cleavage at position 586. In contrast to cleavable htt, caspase-resistant htt with an expanded polyglutamine tract has reduced toxicity in apoptotically stressed neuronal and nonneuronal cells and forms aggregates at a much reduced frequency. These results suggest that inhibiting caspase cleavage of htt may therefore be of potential therapeutic benefit in Huntington's disease.
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PMID:Inhibiting caspase cleavage of huntingtin reduces toxicity and aggregate formation in neuronal and nonneuronal cells. 1077 Sep 29

Huntington disease is an autosomal dominant neurodegenerative disease with no effective treatment. Minocycline is a tetracycline derivative with proven safety. After ischemia, minocycline inhibits caspase-1 and inducible nitric oxide synthetase upregulation, and reduces infarction. As caspase-1 and nitric oxide seem to play a role in Huntington disease, we evaluated the therapeutic efficacy of minocycline in the R6/2 mouse model of Huntington disease. We report that minocycline delays disease progression, inhibits caspase-1 and caspase-3 mRNA upregulation, and decreases inducible nitric oxide synthetase activity. In addition, effective pharmacotherapy in R6/2 mice requires caspase-1 and caspase-3 inhibition. This is the first demonstration of caspase-1 and caspase-3 transcriptional regulation in a Huntington disease model.
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PMID:Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. 1101 10

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by chorea, psychiatric disturbances, and dementia. It is caused by a polyglutamine repeat expansion in the huntingtin protein. The striatum is a major site of neuronal loss in HD, but the mechanisms underlying the neurodegenerative process have not been established. Systemic administration of the succinate dehydrogenase inhibitor 3-nitropropionic acid (3NP) to rodents results in motor dysfunction and degeneration of striatal neurons with features similar to those of HD. Here we report that levels of prostate apoptosis response-4 (Par-4; a protein recently linked to neuronal apoptosis) increase in striatum, and to a lesser extent in cortex and hippocampus, after systemic administration of 3NP to adult rats. The increase in Par-4 levels occurred within 6 h of 3NP administration and was followed by an increase in caspase activation which preceded neuronal loss. Exposure of cultured primary striatal neurons to 3NP induced a rapid increase of Par-4 levels and caspase activation. Treatment of striatal neurons with a Par-4 antisense oligonucleotide blocked Par-4 induction by 3NP, suppressed caspase activation, and attenuated neuronal apoptosis. The caspase-3 inhibitor DEVD suppressed 3NP-induced apoptosis of striatal neurons, but did not prevent induction of Par-4, indicating that Par-4 acts upstream of caspase-3 activation in the cell death pathway. Our results suggest that Par-4 plays an important role in the degeneration of striatal neurons in an experimental model of HD.
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PMID:Participation of par-4 in the degeneration of striatal neurons induced by metabolic compromise with 3-nitropropionic acid. 1096 80


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