title: P38 MAPK is involved in enhanced NMDA receptor-dependent excitotoxicity in YAC transgenic mouse model of Huntington disease.
abstract: Huntington disease (HD) is a dominantly inherited neurodegenerative disease caused by a polyglutamine (polyQ) expansion in the protein huntingtin (htt). Previous studies have shown enhanced N-methyl-d-aspartate (NMDA)-induced excitotoxicity in neuronal models of HD, mediated in part by increased NMDA receptor (NMDAR) GluN2B subunit binding with the postsynaptic density protein-95 (PSD-95). In cultured hippocampal neurons, the NMDAR-activated p38 Mitogen-activated Protein Kinase (MAPK) death pathway is disrupted by a peptide (Tat-NR2B9c) that uncouples GluN2B from PSD-95, whereas NMDAR-mediated activation of c-Jun N-terminal Kinase (JNK) MAPK is PSD-95-independent. To investigate the mechanism by which Tat-NR2B9c protects striatal medium spiny neurons (MSNs) from mutant htt (mhtt)-enhanced NMDAR toxicity, we compared striatal tissue and cultured MSNs from presymptomatic yeast artificial chromosome (YAC) mice expressing htt with 128 polyQ (YAC128) to those from YAC18 and/or WT mice as controls. Similar to the previously published shift of GluN2B-containing NMDARs to extrasynaptic sites, we found increased PSD-95 localization as well as elevated PSD-95-GluN2B interactions in the striatal non-PSD (extrasynaptic) fraction from YAC128 mice. Notably, basal levels of both activated p38 and JNK MAPKs were elevated in the YAC128 striatum. NMDA stimulation of acute slices increased activation of p38 and JNK in WT and YAC128 striatum, but Tat-NR2B9c pretreatment reduced only the p38 activation in YAC128. In cultured MSNs, p38 MAPK inhibition reduced YAC128 NMDAR-mediated cell death to WT levels, and occluded the Tat-NR2B9c peptide protective effect; in contrast, inhibition of JNK had a similar protective effect in cultured MSNs from both WT and YAC128 mice. Our results suggest that altered activation of p38 MAPK contributes to mhtt enhancement of GluN2B/PSD-95 toxic signaling.
authors.affiliation: Graduate Program in Neuroscience, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jing
authors.initials: J
authors.lastname: Fan
authors.forename: Clare M
authors.initials: CM
authors.lastname: Gladding
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.forename: Lily Y J
authors.initials: LY
authors.lastname: Zhang
authors.forename: Alexandra M
authors.initials: AM
authors.lastname: Kaufman
authors.forename: Austen J
authors.initials: AJ
authors.lastname: Milnerwood
authors.forename: Lynn A
authors.initials: LA
authors.lastname: Raymond
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D002540:Cerebral Cortex / Q000166:cytology; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D018920:Coculture Techniques; D003342:Corpus Striatum / Q000473:pathology*; D004195:Disease Models, Animal; D000076122:Disks Large Homolog 4 Protein; D004622:Embryo, Mammalian; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D051528:Guanylate Kinases / Q000378:metabolism; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000473:pathology*; D047468:Immunoprecipitation / Q000379:methods; D020287:In Situ Nick-End Labeling; D008164:Luminescent Proteins / Q000235:genetics; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics; D010455:Peptides / Q000235:genetics / Q000494:pharmacology; D016194:Receptors, N-Methyl-D-Aspartate / Q000737:chemistry / Q000378:metabolism*; D013347:Subcellular Fractions / Q000187:drug effects / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D001426:Bacterial Proteins; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D004791:Enzyme Inhibitors; C086055:HTT protein, human; D000071058:Huntingtin Protein; D008164:Luminescent Proteins; D008565:Membrane Proteins; C120997:NR2A NMDA receptor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D010455:Peptides; D016194:Receptors, N-Methyl-D-Aspartate; C054562:yellow fluorescent protein, Bacteria; C097188:polyglutamine; D016202:N-Methylaspartate; C542597:Tat-NR2B9c; D048051:p38 Mitogen-Activated Protein Kinases; D051528:Guanylate Kinases