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.
abstract: Cellular prion protein (PrP(C)) is a glycosyl-phosphatidylinositol-anchored glycoprotein. When mutated or misfolded, the pathogenic form (PrP(SC)) induces transmissible spongiform encephalopathies. In contrast, PrP(C) has a number of physiological functions in several neural processes. Several lines of evidence implicate PrP(C) in synaptic transmission and neuroprotection since its absence results in an increase in neuronal excitability and enhanced excitotoxicity in vitro and in vivo. Furthermore, PrP(C) 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 Prnp(o/o)Jnk3(o/o) mice were not affected by KA. Pharmacological blockage of JNK3 activity impaired PrP(C)-dependent neurotoxicity. Furthermore, our results indicate that JNK3 activation depends on the interaction of PrP(C) 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 PrP(C). 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 PrP(C) against KA is due to its ability to modulate GluR6/7-mediated neurotransmission and hence JNK3 activation.
authors.affiliation: Molecular and Cellular Neurobiotechnology, Institute for Bioengineering of Catalonia, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Carulla
authors.forename: Ana
authors.initials: A
authors.lastname: Bribián
authors.forename: Alejandra
authors.initials: A
authors.lastname: Rangel
authors.forename: Rosalina
authors.initials: R
authors.lastname: Gavín
authors.forename: Isidro
authors.initials: I
authors.lastname: Ferrer
authors.forename: Carme
authors.initials: C
authors.lastname: Caelles
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Del Río
authors.forename: Franc
authors.initials: F
authors.lastname: Llorens
mesh_terms: D000818:Animals; D016923:Cell Death / Q000187:drug effects; D000076122:Disks Large Homolog 4 Protein; D015536:Down-Regulation; D004789:Enzyme Activation; D004827:Epilepsy / Q000139:chemically induced* / Q000517:prevention & control*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D015870:Gene Expression; D051528:Guanylate Kinases / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048057:Mitogen-Activated Protein Kinase 10 / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*; D061251:Primary Cell Culture; D000072002:Prion Proteins; D011328:Prions / Q000235:genetics; D011485:Protein Binding; D018092:Kainic Acid Receptors / Q000378:metabolism*; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor
chemical_list: D000076122:Disks Large Homolog 4 Protein; D048049:Extracellular Signal-Regulated MAP Kinases; D051528:Guanylate Kinases; D007608:Kainic Acid; D008565:Membrane Proteins; D048057:Mitogen-Activated Protein Kinase 10; D018621:PrPC Proteins; D000072002:Prion Proteins; D011328:Prions; D018092:Kainic Acid Receptors; D000097806:GluK2 Kainate Receptor; D000097808:GluK3 Kainate Receptor; C501447:Dlg4 protein, mouse; C512657:Prnp protein, mouse