Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.22.56 (caspase-3)
 35,750 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

The mutation underlying Huntington disease (HD) is CAG expansion beyond 35 repeats within a novel gene. Recently, new insights into the role of the HD protein (huntingtin) in the pathogenesis of HD have emerged. The CAG is translated and expression of mutant huntingtin is essential for neuronal death. Huntingtin is crucial for normal development and may be regarded as a cell survival gene. Huntingtin is specifically cleaved during apoptosis by a key cysteine protease, apopain, known to play a pivotal role in apoptotic cell death. The rate of cleavage is enhanced by longer polyglutamine tracts, suggesting that inappropriate apoptosis underlies HD. Recently, three proteins have been identified and have been shown specifically to interact with huntingtin, two of these interactions being influenced by CAG length. Several different approaches to develop an animal model for HD include cDNA and YAC transgenics, as well as 'knock-in' strategies. Such a model will be critical for the understanding of the natural history of HD and for the testing of new therapeutic modalities.
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PMID:Huntington disease: new insights into the relationship between CAG expansion and disease. 887 48

Huntington's Disease (HD) is caused by expansion of a CAG trinucleotide beyond 35 repeats within the coding region of a novel gene. Recently, new insights into the relationship between CAG expansion in the HD gene and pathological mechanisms have emerged. Survival analysis of a large cohort of affected and at-risk individuals with CAG sizes between 39 and 50 repeats have yielded probability curves of developing HD symptoms and dying of HD by a certain age. Animals transgenic for the first exon of huntingtin with large CAG repeats lengths have been reported to have a complex neurological phenotype that bears interesting similarities and differences to HD. The repertoire of huntingtin-interacting proteins continues to expand with the identification of HIP1, a protein whose yeast homologues have known functions in regulating events associated with the cytoskeleton. The ability of huntingtin to interact with two of its four known protein partners appears to be influenced by CAG length. Caspase 3 (apopain), a key cysteine protease known to play a seminal role in neural apoptosis, has also been demonstrated to specifically cleave huntingtin in a CAG length-dependent manner. Many of these features are combined in a model suggesting mechanisms by which the pathogenesis of HD may be initiated. The development of appropriate in vitro and animal models for HD will allow the validity of these models to be tested.
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PMID:Toward understanding the molecular pathology of Huntington's disease. 921 79

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

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

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'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

Expansion of a polyglutamine repeat in huntingtin causes Huntington's disease (HD). Although full-length huntingtin is predominantly distributed in the cytoplasm, N-terminal fragments of huntingtin with expanded polyglutamine tracts are able to accumulate in the nucleus and kill neurons through apoptotic pathways. Transgenic mice expressing N-terminal mutant huntingtin show intranuclear huntingtin accumulation and develop progressive neurological symptoms. Inhibiting caspase-1 can prolong the survival of these HD mice. How intranuclear huntingtin is associated with caspase activation and apoptosis is unclear. Here we report that intranuclear huntingtin induces the activation of caspase-3 and the release of cytochrome c from mitochondria in cultured cells. As a result, cells expressing intranuclear huntingtin undergo apoptosis. We show that intranuclear huntingtin increases the expression of caspase-1, which may in turn activate caspase-3 and trigger apoptosis. We propose that the increased level of caspase-1 induced by intranuclear huntingtin contributes to HD-associated cell death.
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PMID:Intranuclear huntingtin increases the expression of caspase-1 and induces apoptosis. 1109 62

Huntington Disease (HD) results from polyglutamine expansion within the N-terminus of huntingtin. We have produced yeast artificial chromosome (YAC) transgenic mice expressing normal (YAC18) and mutant (YAC46 and YAC72) human huntingtin in a developmentally appropriate and tissue-specific manner identical to the pattern of expression of endogenous huntingtin. YAC46 and YAC72 mice show early electrophysiological abnormalities indicating neuronal cytoplasmic dysfunction prior to developing nuclear inclusions or neurodegeneration. YAC72 mice display a hyperkinetic movement disorder by 7 months of age, and have evidence for selective and specific degeneration of medium spiny neurons in the lateral striatum by 12 months of age. A key molecular feature of pathology of these YAC72 mice is cleavage of huntingtin in the cytoplasm following by translocation of the resulting huntingtin N-terminal fragments into the nucleus of striatal neurons. Increasing nuclear localization of huntingtin N-terminal fragments within medium spiny neurons of the striatum occurs concomitantly with the onset of selective neurodegeneration. Because huntingtin is a caspase substrate and truncated huntingtin fragments are toxic in vitro, inhibiting caspase cleavage of huntingtin may be of potential therapeutic benefit in HD. We show that caspase inhibitors eliminate huntingtin cleavage in cells and protects them from an apoptotic stress. We also identify caspase-6 and caspase-3 cleavage sites in huntingtin and demonstrate that neuronal and non-neuronal cells expressing a caspase-resistant huntingtin with an expanded polyglutamine tract are less susceptible to apoptosis and aggregate formation. These results suggest that caspase cleavage of huntingtin may be a crucial step in aggregate formation and neurotoxicity in HD.
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PMID:Huntington disease: new insights on the role of huntingtin cleavage. 1112


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