Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.22.56 (caspase-3)
 35,750 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

In this study we analysed the effect of Bcl-2 on the cytotoxicity induced by the amyloid-beta (Abeta(25-35)) and prion (PrP(106-126)) peptides by using GT1-7puro and GT1-7bcl-2 (overexpressing the anti-apoptotic protein Bcl-2) neural cells. Exposure to Abeta(25-35) (1-5 microM) and PrP(106-126) (25 microM) caused a decrease in cell viability, as determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. These data were correlated with Abeta(25-35) and PrP(106-126)-induced activation of caspase-9, which is linked to the mitochondrial death pathway, and the activation of the effector caspase-3, suggesting cell death by apoptosis. Furthermore, Bcl-2 overexpression protected from loss of cell viability and caspase-9 and -3 activation induced by Abeta(25-35) and PrP(106-126), showing that Bcl-2 is neuroprotective against apoptotic cell death caused by amyloidogenic peptides.
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PMID:Bcl-2 overexpression protects against amyloid-beta and prion toxicity in GT1-7 neural cells. 1805 55

Dietary supplements containing polyunsaturated fatty acids (PUFA) are frequently taken for their perceived health benefits including a possible reduction in cognitive decline in the elderly. Here we report that pre-treatment with docosahexaenoic acid (DHA) or eicosapentaenoic acid (EPA) significantly reduced the survival of cortical or cerebellar neurons incubated with HuPrP82-146, a peptide derived from the prion protein, or with Abeta 1-42, a peptide found in Alzheimer's disease. Treatment with DHA or EPA reduced the free cholesterol content of neuronal membranes. This did not affect the amount of FITC-HuPrP82-146 ingested by neurons, but increased the kinetics of incorporation. In untreated neurons, FITC-HuPrP82-146 migrated to caveolin-1 containing lipid rafts. The addition of HuPrP82-146 also triggered the migration of cytoplasmic phospholipase A2 (cPLA2) into caveolin-1 containing rafts, and increased prostaglandin E2 production. Activation of cPLA2 and prostaglandin E2 production were both increased in neurons pre-treated with DHA. These results are consistent with DHA or EPA altering cell membranes resulting in increased amounts of HuPrP82-146 localising to caveolin-1 containing rafts, increased activation of cPLA2, prostaglandin E2 production, caspase-3 activity and reduced neuronal survival. Such observations raise the possibility that some PUFA supplements may accelerate neuronal loss in the terminal stages of prion or Alzheimer's diseases.
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PMID:Docosahexaenoic and eicosapentaenoic acids increase neuronal death in response to HuPrP82-146 and Abeta 1-42. 1835 80

The transmissible spongiform encephalopathies develop following the conversion of a host-encoded protein (PrP(C)) into abnormally folded, disease-related isoforms (PrP(Sc)). Here we report that three acyl-coenzyme A:cholesterol acyltransferase (ACAT) inhibitors, TMP-153, FR179254 or YIC-C8-434, were more toxic to prion-infected neuronal cell lines (ScGT1 and ScN2a cells) than to their uninfected equivalents (GT1 and N2a cells). The toxicity of ACAT inhibitors for ScGT1 cells was not reversed by the addition of cholesterol esters, rather it was increased by the addition of free cholesterol indicating that the toxicity of ACAT inhibitors was related to the increased free cholesterol content of cells rather than reduced amounts of cholesterol esters. This hypothesis was strengthened by the observation that the addition of free cholesterol killed ScGT1, but not GT1 cells. Treatment with ACAT inhibitors increased caspase-3 activity and prostaglandin E(2) production in ScGT1 cells but not in GT1 cells. The addition of the phospholipase A(2) (PLA(2)) inhibitors (AACOCF(3) or MAFP) reduced prostaglandin E(2) production and protected ScGT1 cells against the toxicity of ACAT inhibitors. These results indicate that cholesterol esterification is an important cellular response that reduces PrP(Sc)-induced activation of PLA(2) and protects against cell death in ScGT1 cells.
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PMID:Cholesterol esterification reduces the neurotoxicity of prions. 1844 39

Neurodegeneration and gliosis are the main neuropathological features of prion diseases. However, the molecular mechanisms involved in these processes remain unclear. Several studies have demonstrated changes in the expression of apoptotic factors and inflammatory cytokines in animals with experimental infection. Here we present the expression profiles of 15 genes implicated in the intrinsic and extrinsic apoptotic pathways in the central nervous systems of sheep naturally infected with scrapie. Expression changes obtained by real-time RT-PCR were also compared with the extent of classical scrapie lesions, such as prion deposition, neuronal vacuolisation, spongiosis, and astrogliosis as well as with the activation of caspase-3, using a stepwise regression. The results suggest that the factors assessed participate in apoptotic or inflammatory functions, depending on the affected area. The mitochondrial apoptosis pathway was associated with prion deposition in the prefrontal cortex (the less affected area), and with activation of caspase-3-mediated cell death via over-expression of BAK. In addition to its known association with astroglial activation, the extrinsic apoptosis pathway was also related to cell death and neuronal vacuolisation.
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PMID:Distinct spatial activation of intrinsic and extrinsic apoptosis pathways in natural scrapie: association with prion-related lesions. 1940 Nov 42

Different neurodegenerative disorders like prion disease, is caused by protein misfolding conformers. Reverse-transfected cytosolic prion protein (PrP) and PrP expressed in the cytosol have been shown to be neurotoxic. To investigate the possible mechanism of neurotoxicity due to accumulation of PrP in cytosol, a PrP mutant lacking the signal and GPI (CytoPrP) was introduced into the SH-SY5Y cell. MTT and trypan blue assays indicated that the viability of cells expressing CytoPrP was remarkably reduced after treatment of MG-132. Obvious apoptosis phenomena were detected in the cells accumulated with CytoPrP, including loss of mitochondrial transmembrane potential, increase of caspase-3 activity, more annexin V/PI-double positive-stained cells and reduced Bcl-2 level. Moreover, DNA fragmentation and TUNEL assays also revealed clear evidences of late apoptosis in the cells accumulated CytoPrP. These data suggest that the accumulation of CytoPrP in cytoplasm may trigger cell apoptosis, in which mitochondrial relative apoptosis pathway seems to play critical role.
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PMID:Cytosolic prion protein induces apoptosis in human neuronal cell SH-SY5Y via mitochondrial disruption pathway. 1964 43

Doppel (Dpl) is a recently identified prion (PrP)-like protein due to the structural and biochemical similarities, however, its natural function and pathogenic role in neurodegenerative diseases remains unclear. To investigate the possible pathogenic pathway of Dpl and its structural analog for cell apoptosis, mammalian expressing recombinant plasmids containing human PRND gene encoding the full-length Dpl and a truncated human PRNP gene deleting the sequences encoding the peptide from aa 32 to 121 (PrPDelta32-121) were generated. MTT assays showed the cell viabilities of the human neuroblastoma cell line SH-SY5Y receiving Dpl and PrPDelta32-121 expressing plasmids were remarkably lower. Obvious apoptosis phenomena were observed to be associated with the cells transient expressing Dpl and PrPDelta32-121, including reduced mitochondrial transmembrane potential (psim), decreased pro-caspase-3 quantity, more numbers of annexin V- and annexin V/PI-double-stained cells and depressed Bcl-2 level. Moreover, we also found that the Dpl- and PrPDelta32-121-induced cytotoxicities and relevant apoptotic events in SH-SY5Y cells could be fully antagonized by co-expression of the human full-length PrP. These data highly indicate that cytotoxicity induced by the expression of Dpl and truncated PrP in neural derived cells are closely related with the apoptosis process, probably triggering the mitochondrial pathway. It also implies that the cell-benefit activity of the full-length PrP may result from its anti-apoptosis capacity.
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PMID:Transient expressions of doppel and its structural analog prionDelta32-121 in SH-SY5Y cells caused cytotoxicity possibly by triggering similar apoptosis pathway. 1972 51

The pathogenesis of prion diseases includes synapse degeneration and neuronal death. Here we report that pre-treatment with glucosamine-phosphatidylinositol (glucosamine-PI), a synthetic analogue of the glycosylphosphatidylinositol (GPI) anchor that attaches the prion protein (PrP(C)) to plasma membranes, increased the resistance of cultured cortical neurones to the toxic effects of the prion-derived peptide PrP82-146. Pre-treatment with glucosamine-PI reduced the PrP82-146 induced activation of cytoplasmic phospholipase A(2) (cPLA(2)), activation of caspase-3 and synapse degeneration. The addition of glucosamine-PI significantly increased the amount of cholesterol within neuronal membranes consistent with the hypothesis that GPI anchors sequester cholesterol. Whereas in untreated neurones PrP82-146 was found within lipid rafts, in glucosamine-PI treated neurones most PrP82-146 was found in the normal cell membrane and was rerouted into the lysosomes. Complex GPI anchors isolated from PrP(C), Thy-1 or CD55 were also protective against PrP82-146. We conclude that glucosamine-PI, or isolated GPI anchors, can modify local membrane micro-environments that are important in the initiation of signalling events that mediate PrP82-146 induced neurodegeneration.
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PMID:A glycosylphosphatidylinositol analogue reduced prion-derived peptide mediated activation of cytoplasmic phospholipase A2, synapse degeneration and neuronal death. 2039 81

Prion diseases are fatal neurodegenerative disorder associated with the conversion of the cellular isoform of the prion protein (PrP(C)) into the infectious scrapie isoform (PrP(Sc)). Deposition of misfolded prion proteins (PrP) on certain regions of brain can result in prion diseases. As a membrane-bound chaperone of the endoplasmic reticulum (ER), calnexin ensures the proper folding and quality control of newly synthesized proteins. Using purified components in vitro, calnexin associated with many proteins and suppresses their thermal aggregation effectively. We for the first time analyzed PrP-calnexin interaction. The immunoprecipitation, confocal microscope and native polyacrylamide-gel electrophoresis results indicated that calnexin could bind PrP both in vitro and in vivo. The turbidity result showed that calnexin could supress thermal aggregation of PrP. MTT, flow cytometry (FCM) and caspase activity studies demonstrated that calnexin prevent caspase-3-mediated cytotoxicity induced by PrP. These results implied that calnexin is potentially beneficial for the resistance of prion diseases.
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PMID:Calnexin inhibits thermal aggregation and neurotoxicity of prion protein. 2050 17

Prion diseases associated with the conversion of the cellular prion protein (PrP(C)) to the misfolded isoform (PrP(Sc)), affect the central nervous system (CNS) of humans and animals. Resveratrol, an activator of class III histone deacetylase SIRT1, is important in attenuating cellular injury and oxidative stress. The present study investigated the effects of SIRT1 activation on prion protein-mediated neuronal cell death and examined its possible signals in intracellular apoptotic pathways. Resveratrol treatment significantly increased both SIRT1 protein expression and SIRT1 activity and protected neuronal cells against PrP (106-126)-induced cell death. Resveratrol-mediated SIRT1 activation decreased the acetylation of p53 and p65 induced by prion protein and SIRT1 inhibitor. SIRT1 activation also inhibited PrP (106-126)-mediated p38 mitogen-activating protein kinase (MAPK) activation and caspase-3 cleavage, and increased the expression of anti-apoptotic Bcl-xL protein. Furthermore, SIRT1 overexpression by using adenoviral vector protected neuronal cells against PrP (106-126). These results indicate that resveratrol inhibits PrP (106-126)-induced neuronal cell death by regulating SIRT1 activity and SIRT-related signaling, and suggest that prion-related disease may be attenuated by SIRT1 activation or by intake of SIRT1-activating molecules.
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PMID:SIRT1, a histone deacetylase, regulates prion protein-induced neuronal cell death. 2107 97


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