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)

Prion diseases are characterised by severe neural lesions linked to the presence of an abnormal protease-resistant isoform of cellular prion protein (PrPc). The peptide PrP(106-126) is widely used as a model of neurotoxicity in prion diseases. Here, we examine in detail the intracellular signalling cascades induced by PrP(106-126) in cortical neurons and the participation of PrPc. We show that PrP(106-126) induces the activation of subsets of intracellular kinases (e.g., ERK1/2), early growth response 1 synthesis and induces caspase-3 activity, all of which are mediated by nicotinamide adenine dinucleotide phosphate hydrogen-oxidase activity and oxidative stress. However, cells lacking PrPc are similarly affected after peptide exposure, and this questions the involvement of PrPc in these effects.
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PMID:PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc. 1602 5

The molecular basis for neuronal death in prion disease is not established, but putative pathogenic roles for both disease-related prion protein (PrP(Sc)) and accumulated cytosolic PrP(C) have been proposed. Here we report that only prion-infected neuronal cells become apoptotic after mild inhibition of the proteasome, and this is strictly dependent upon sustained propagation of PrP(Sc). Whereas cells overexpressing PrP(C) developed cytosolic PrP(C) aggregates, this did not cause cell death. In contrast, only in prion-infected cells, mild proteasome impairment resulted in the formation of large cytosolic perinuclear aggresomes that contained PrP(Sc), heat shock chaperone 70, ubiquitin, proteasome subunits, and vimentin. Similar structures were found in the brains of prion-infected mice. PrP(Sc) aggresome formation was directly associated with activation of caspase 3 and 8, resulting in apoptosis. These data suggest that neuronal propagation of prions invokes a neurotoxic mechanism involving intracellular formation of PrP(Sc) aggresomes. This, in turn, triggers caspase-dependent apoptosis and further implicates proteasome dysfunction in the pathogenesis of prion diseases.
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PMID:Disease-related prion protein forms aggresomes in neuronal cells leading to caspase activation and apoptosis. 1615 91

An immunohistochemical and histochemical study was carried out on the brains of nine cases of BSE-diagnosed cattle as part of the surveillance plan in Catalonia, Spain. The animals had no clinical symptoms reported and were thus at early stages of the disease. The first part of the study consisted of a characterization of PrP(BSE) deposits throughout the encephalon. The behaviour of the different immuno-labelling patterns was analysed and tropism of some patterns towards certain brain areas was described. This tropism is principally directed to the brain stem region; however, an association of the stellate pattern was found with areas where PrP(BSE) is deposited less abundantly, such as the cerebral cortex. Secondly, distinct pathogenesis mechanisms that take place in the early stages of BSE, which would include these cases were investigated. This study describes the glial response to the presence of PrP(BSE) (using antibodies against astrocytic glial fibrillary acidic protein and lectin from Griffonia simplicifolia to identify microglia), the presence of mild oxidative stress phenomena (antibodies against metallothioneins I and II and against nitrated aminoacidic residues: nitrotyrosine), the apparent absence of apoptotic cellular death (cleaved caspase 3) and the preservation of synaptic proteins synaptophysin and small synaptosome-associated 25 kDa protein immuno-labelling. Finally, no alteration of the extra-cellular matrix was detected with the use of Wisteria floribunda agglutinin, a marker for perineuronal nets.
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PMID:Immunohistochemical approach to the pathogenesis of bovine spongiform encephalopathy in its early stages. 1640 59

Although apoptosis has been implicated in the neuronal loss observed in prion diseases, the participation of apoptosis-related factors, like the Bcl-2 family of proteins, is still not clear. Moreover, there are conflicting data concerning the major role of apoptosis in the neuropathology associated with transmissible spongiform encephalopathies. Many studies have been developed in vitro or in experimentally infected animal models but, at present, little is known about this process in natural spontaneous and acquired prion diseases. In this work, the implication of Bax and Bcl-2 has been investigated by the analysis of their expression and protein distribution in medulla oblongata of naturally scrapie-infected sheep. Moreover, their spatial relationship with PrP(Sc) deposition, neuronal vacuolation and neuropil spongiosis has also been analysed as well as the possible induction of neuronal apoptosis in this model. Real Time RT-PCR showed overexpression of the pro-apoptotic gene Bax in scrapie medullas, and immunohistochemistry confirmed its accumulation. No variation of Bcl-2 was observed at the level of gene expression or protein production. Bax distribution, PrP(Sc) deposition, neuronal vacuolation and spongiosis were quantified in different medulla oblongata nuclei and their spatial relationship was evaluated. Bax staining showed a positive correlation with prion deposition, suggesting that this factor is involved in prion neurotoxicity in our natural model. Despite Bax overexpression, neuronal apoptosis was revealed neither by TUNEL nor by immunohistochemical detection of the activated form of caspase-3. This lack of apoptosis could be attributed to the relatively low number of neurons in this area or to the existence of neuroprotective mechanisms in medulla oblongata motor neurons.
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PMID:Correlation between Bax overexpression and prion deposition in medulla oblongata from natural scrapie without evidence of apoptosis. 1680 9

The transition of prion protein from a mainly alpha-structured isoform (PrPC) to a beta sheet-containing protein (PrPSc) represents a major pathogenetic mechanism in prion diseases. To study the role of PrP structural conformation in prion-dependent neurodegeneration, we analysed the neurotoxicity of PrP in alpha and beta conformations, using a recombinant protein encompassing amino acids 90-231 of the human PrP (hPrP90-231). Using controlled thermal denaturation (53 degrees C, 1h) we converted hPrP90-231 in a structural isoform displaying PrPSc-related characteristics: high beta sheet content, increased aggregability and a slight increase in the resistance to protease K. In virtue of these structural changes, hPrP90-231 powerfully affected the survival of SH-SY5Y cells, inducing a caspase-3 and p38- dependent apoptosis. Conversely, in the native alpha-helix-rich conformation, hPrP90-231 did not show significant cell toxicity. The relationship between the structural state of hPrP90-231 and its neurotoxicity was demonstrated, inducing the thermal denaturation of the peptide in the presence of Congo red that prevented both the transition of hPrP90-231 into a beta-rich isoform and the acquisition of toxic properties. In conclusion, we report that the toxicity of hPrP90-231 is dependent on its three-dimensional structure, as is supposed to occur for the pathogen PrP during TSE.
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PMID:Conformation dependent pro-apoptotic activity of the recombinant human prion protein fragment 90-231. 1683 1

The cellular prion protein (PrP(c)) undergoes various endopro-teolytic attacks within its N-terminal domain, leading to the production of C-terminal fragments (C) tethered to the plasma membrane and soluble N-terminal peptides (N). One of these cleavages occurs at position 110/111, thereby generating C1 and N1 products. We have reported that disintegrins ADAM-10, -9, and -17 participate either directly or indirectly to this proteolytic event. An alternative proteolytic event taking place around residue 90 yields C2 and N2 fragments. The putative function of these proteolytic fragments remained to be established. We have set up two novel human embryonic kidney 293 cell lines stably overexpressing either C1 or C2. We show that C1 potentiates staurosporine-induced caspase-3 activation through a p53-dependent mechanism. Thus, C1 positively controls p53 transcription and mRNA levels and increases p53-like immunoreactivity and activity. C1-induced caspase-3 activation remained unaffected by the blockade of endocytosis in HEK 293 cells and was abolished in p53-deficient fibroblasts. Conversely, overexpression of the C2 fragment did not significantly sensitize HEK 293 cells to apoptotic stimuli and did not modify p53 mRNA levels or activity. Therefore, the nature of the proteolytic cleavage taking place on PrP(c) yielded C-terminal catabolites with distinct function and could be seen as a switch mechanism controlling the function of the PrP(c) in cell survival.
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PMID:The C-terminal products of cellular prion protein processing, C1 and C2, exert distinct influence on p53-dependent staurosporine-induced caspase-3 activation. 1712 21

Prnp knockout mice that overexpress an amino-truncated form of PrPc (deltaPrP) are ataxic and display cerebellar cell loss and premature death. Studies on the molecular and intracellular events that trigger cell death in these mutants may contribute to elucidate the functions of PrPc and to the design of treatments for prion disease. Here we examined the effects of Bcl-2 overexpression in neurons on the development of the neurological syndrome and cerebellar pathology of deltaPrP. We show that deltaPrP overexpression activates the stress-associated kinases ERK1-2 in reactive astroglia, p38 and the phosphorylation of p53, which leads to the death of cerebellar neurons in mutant mice. We found that the expression of deltaPrP in cell lines expressing very low levels of PrPc strongly induces the activation of apoptotic pathways, thereby leading to caspase-3 activation and cell death, which can be prevented by coexpressing Bcl-2. Finally, we corroborate in vivo that neuronal-directed Bcl-2 overexpression in deltaPrP mice (deltaPrP Bcl-2) markedly reduces caspase-3 activation, glial activation, and neuronal cell death in cerebellum by improving locomotor deficits and life expectancy.
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PMID:Bcl-2 overexpression delays caspase-3 activation and rescues cerebellar degeneration in prion-deficient mice that overexpress amino-terminally truncated prion. 1749 93

A normal prion protein (PrPc) is converted to a proteaseresistant isoform by an apparent self-propagating activity in transmissible spongiform encephalopathy, a neurodegenerative disease. The cDNA encoding open reading frame (ORF) of the bovine prion protein gene (Prnp) was cloned from Korean cattle by PCR, and was transfected into Chinese hamster ovary (CHO-K1) cells using lipofectamine. The gene expression of the cloned cDNA was confirmed by RT-PCR and Western blotting with the monoclonal antibody, 6H4. Cellular changes in the transfected CHO-K1 cells were investigated using parameters such as MTT, lactate dehydrogenase (LDH), and superoxide dismutase (SOD) activities, as well as nitric oxide (NO) production, and an apoptosis assay. In the MTT and LDH assays, the bovine PrnP-transfectant showed a lower proliferation rate than the wild-type (p < 0.05). Production of NO, after LPS or ConA stimulation, was not detected in either transfectants or CHO-K1 cells. In SOD assay under ConA stimulation, the SOD activity of transfectants was 10 times higher than that of CHO-K1 cells at 6 h after treatment (p < 0.05). The genomic DNA of both the transfectants and control cells began to be fragmented at 6 h after treatment with cyclohexamide. Caspase-3 activity was reduced by transfection with the bovine Prnp (p < 0.05). Conclusively, the viability of transfectants expressing exogenous bovine Prnp was decreased while the capacities for cellular protection against antioxidative stress and apoptosis were increased.
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PMID:Biological characteristics of Chinese hamster ovary cells transfected with bovine Prnp. 1751 65

Bax is a pro-apoptotic member of the Bcl-2 family that plays an important role in neuronal apoptosis. However, the results are controversial, especially regarding its function in the apoptosis involved in prion diseases. This work analyzes the gene expression and protein distribution of Bax in the central nervous systems of sheep naturally infected with scrapie. Gene expression profiling, obtained by means of real-time RT-PCR analysis, has shown a significant over-expression of this pro-apoptotic factor in medulla oblongata and diencephalon, whereas its expression was stable in cerebellum and prefrontal cortex. Immunohistochemistry confirmed the expression results and extended the investigation to 13 different regions. A high degree of variability was found in Bax immunoreactivity, mainly in the scrapie group, which also corresponded to the degree of PrP(Sc) deposition. Despite this variability, qualitative differences were found between scrapie and control groups. Intraneuronal reactivity for Bax was mainly observed in the spinal cord, brain stem, hypothalamus, and colicullus of scrapie animals, whereas controls displayed immunoreactivity almost exclusively in the neuropile. Moreover, a significant positive correlation was observed between Bax and prion deposition. Despite Bax over-expression, the activated form of caspase-3 was never observed in neurons showing apoptotic-like morphology. In contrast, activated caspase-3 staining appeared as cytoplasmic granules in apparently healthy neurons. We conclude that apoptosis either occurs in an extremely low number of neurons or neuroprotective mechanisms arrest the mitochondrial pathway after Bax induction.
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PMID:Differential expression and protein distribution of Bax in natural scrapie. 1794 98

Prion disorders are progressive neurodegenerative diseases characterized by extensive neuronal loss and by the accumulation of the pathogenic form of prion protein, designated PrP(Sc). Recently, we have shown that PrP(106-126) induces endoplasmic reticulum (ER) stress, leading to mitochondrial cytochrome c release, caspase 3 activation and apoptotic death. In order to further clarify the role of mitochondria in ER stress-mediated apoptotic pathway triggered by the PrP peptide, we investigated the effects of PrP(106-126) on the Ntera2 human teratocarcinoma cell line that had been depleted of their mitochondrial DNA, termed NT2 rho0 cells, characterized by the absence of functional mitochondria, as well as on the parental NT2 rho+ cells. In this study, we show that PrP(106-126) induces ER stress in both cell lines, given that ER Ca2+ content is low, glucose-regulated protein 78 levels are increased and caspase 4 is activated. Furthermore, in parental NT2 rho+ cells, PrP(106-126)-activated caspase 9 and 3, induced poly (ADP-ribose) polymerase cleavage and increased the number of apoptotic cells. Dantrolene was shown to protect NT2 rho+ from PrP(106-126)-induced cell death, demonstrating the involvement of Ca2+ release through ER ryanodine receptors. However, in PrP(106-126)-treated NT2 rho0 cells, apoptosis was not able to proceed. These results demonstrate that functional mitochondria are required for cell death as a result of ER stress triggered by the PrP peptide, and further elucidate the molecular mechanisms involved in the neuronal loss that occurs in prion disorders.
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PMID:Involvement of mitochondria in endoplasmic reticulum stress-induced apoptotic cell death pathway triggered by the prion peptide PrP(106-126). 1799 26


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