PrP(106-126) activates neuronal intracellular kinases and Egr1 synthesis through activation of NADPH-oxidase independently of PrPc |
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Authors: | Gavín Rosalina Braun Nathalie Nicolas Oriol Parra Beatriz Ureña Jesus Mariano Mingorance Ana Soriano Eduardo Torres Juan María Aguzzi Adriano del Río José Antonio |
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Affiliation: | Development and Regeneration of the CNS, Department of Cell Biology, Barcelona Science Park - IRB, University of Barcelona, Spain. |
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Abstract: | 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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Keywords: | Ac-DEVD-AFC, Ac-Asp-Glu-Val-Asp-7amino 4trifluoromethyl coumarin AkT, protein kinase B Egr1, early growth response 1 EMMA, European mouse mutant archive ERK1/2, extracellular signal-regulated kinase FYN, protein tyrosine kinase p59 GSK3, glycogen synthase kinase 3 JNK, c-Jun N-terminal kinase MAPK, mitogen-activated protein kinase MEK, Mapk Erk-activating kinase NAC, N-acetyl- smallcaps" >l-cysteine NADPH, nicotinamide adenine dinucleotide phosphate hydrogen PI3K, phosphoinositide-3 kinase Prnp, prion protein gene PrPc, cellular prion protein PrPres, protease-resistant form of prion protein PrPsc, prion protein scrapie form RIPA buffer, radioimmunoprecipitation lysis buffer 1 ROS, reactive oxygen species SDS-PAGE, sodium dodecyl sulphate-polyacrylamide gel electrophoresis SFK, Src-family kinase TPA, phorbol-12-myristate-13-acetate |
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