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Title: Neuroprotective role of PrPC against kainate-induced epileptic seizures and cell death depends on the modulation of JNK3 activation by GluR6/7-PSD-95 binding
Author: Carulla Martí, Patricia
Bribián Arruego, Ana
Rangel Rincones, Alejandra Helena
Gavín Marín, Rosalina
Ferrer, Isidro (Ferrer Abizanda)
Caelles Franch, Carme
Río Fernández, José Antonio del
Llorens Torres, Franc
Keywords: Prions
Malalties per prions
Prion diseases
Issue Date: 29-Jun-2011
Publisher: American Society for Cell Biology
Abstract: Cellular prion protein (PrPC) is a glycosyl-phosphatidylinositol¿anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrPSC) induces transmissible spongiform encephalopathies. In contrast, PrPC has a number of physiological functions in several neural processes. Several lines of evidence implicate PrPC in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrPC has been implicated in the inhibition of N-methyl-D-aspartic acid (NMDA)¿mediated neurotransmission, and prion protein gene (Prnp) knockout mice show enhanced neuronal death in response to NMDA and kainate (KA). In this study, we demonstrate that neurotoxicity induced by KA in Prnp knockout mice depends on the c-Jun N-terminal kinase 3 (JNK3) pathway since Prnpo/oJnk3o/o mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrPC-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrPC with postsynaptic density 95 protein (PSD-95) and glutamate receptor 6/7 (GluR6/7). Indeed, GluR6¿PSD-95 interaction after KA injections was favored by the absence of PrPC. Finally, neurotoxicity in Prnp knockout mice was reversed by an AMPA/KA inhibitor (6,7-dinitroquinoxaline-2,3-dione) and the GluR6 antagonist NS-102. We conclude that the protection afforded by PrPC against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.
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It is part of: Molecular Biology of the Cell, 2011, vol. 22, núm. 17, p. 3041-3054
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ISSN: 1059-1524
Appears in Collections:Articles publicats en revistes (Bioquímica i Biomedicina Molecular)
Articles publicats en revistes (Biologia Cel·lular, Fisiologia i Immunologia)
Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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