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

• Published in: Molecular biology of the cell Vol. 22; no. 17; pp. 3041 - 3054
• Main Authors: Carulla, Patricia, Bribián, Ana, Rangel, Alejandra, Gavín, Rosalina, Ferrer, Isidro, Caelles, Carme, Del Río, José Antonio, Llorens, Franc
• Format: Journal Article
• Language: English
• Published: United States American Society for Cell Biology 01.09.2011; The American Society for Cell Biology
• Subjects: alpha -Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; Animals; c-Jun amino-terminal kinase; Cell death; Cell Death - drug effects; Disks Large Homolog 4 Protein; Down-Regulation; Enzyme Activation; Epilepsy; Epilepsy - chemically induced; Epilepsy - prevention & control; Excitability; Excitotoxicity; Extracellular Signal-Regulated MAP Kinases - metabolism; Gene Expression; GluK2 Kainate Receptor; GluK3 Kainate Receptor; Glutamic acid receptors; Glycoproteins; Guanylate Kinases - metabolism; Hippocampus - metabolism; Hippocampus - pathology; JNK3 protein; Kainic Acid; Malalties per prions; Membrane Proteins - metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; Mitogen-Activated Protein Kinase 10 - genetics; Mitogen-Activated Protein Kinase 10 - metabolism; N-Methyl-D-aspartic acid; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neurotoxicity; Neurotransmission; Postsynaptic density proteins; Primary Cell Culture; Prion protein; Prion Proteins; Prions; Prions - genetics; Prions diseases; Protein Binding; PrPC Proteins - genetics; PrPC Proteins - metabolism; Receptors, Kainic Acid - metabolism; Seizures; Synaptic transmission; Transmissible spongiform encephalopathy
• ISSN: 1059-1524; 1939-4586
• DOI: 10.1091/mbc.E11-04-0321

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.