title: Regulation of proteins affecting NMDA receptor-induced excitotoxicity in a Huntington's mouse model.
abstract: Symptoms of Huntington's disease may be caused by a toxic insult triggered by the mutant human huntingtin (Htt) protein itself, by a maladaptive protective mechanism initiated in response to an insult, or by a combination of these. We observed a protection from N-methyl-d-aspartate (NMDA) receptor-induced excitotoxicity in striata of symptomatic N171-82Q mice, a new transgenic model of Huntington's disease. The goal of this study was to determine if NMDA receptor-mediated signalling pathways are altered in these mice. Multiple proteins of NMDA receptor and dopamine D1 receptor pathways are being regulated in ways predictive of the protection we observe. Although examining NMDA receptor subunit proteins showed no change in NR1, NR2A, or NR2B in the striata of the symptomatic mice, we observed a decrease in phosphorylation of NR1 at Ser897, previously reported to decrease NMDA receptor current. The dopamine D1 receptor, responsible for protein kinase A activation and subsequent phosphorylation of Ser897 of NR1, also showed an age-related decrease. Other proteins regulated in this disease were associated with PSD-95-like scaffolding proteins of the NMDA receptor. Specifically, we observed a decrease in membrane-associated neuronal nitric oxide synthase (nNOS), a decrease in PSD-95-like proteins, which link nNOS to the NMDA receptor complex, and a decrease in citron, a protein associated with dendritic spine formation. From these data, we conclude that the N171-82Q mice seem to be regulating, in a protective direction, many of the known effector pathways of NMDA receptor-induced excitotoxicity. These regulations, although seemingly effective in decreasing neuronal death, may in fact be causing some of the symptoms associated with the disease.
authors.affiliation: Department of Pharmacology, Georgetown University, Washington, DC 20057, USA.
authors.forename: Bryan R
authors.initials: BR
authors.lastname: Jarabek
authors.forename: Robert P
authors.initials: RP
authors.lastname: Yasuda
authors.forename: Barry B
authors.initials: BB
authors.lastname: Wolfe
mesh_terms: D000818:Animals; D015153:Blotting, Western / Q000379:methods; D003342:Corpus Striatum / Q000737:chemistry / Q000378:metabolism*; D000076122:Disks Large Homolog 4 Protein; D051528:Guanylate Kinases; D006816:Huntington Disease / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D023421:Models, Animal; D009419:Nerve Tissue Proteins / Q000032:analysis*; D009474:Neurons / Q000378:metabolism; D009479:Neuropeptides / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000032:analysis; D052248:Nitric Oxide Synthase Type I; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000032:analysis; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D015398:Signal Transduction; D014157:Transcription Factors
chemical_list: C116869:DLG3 protein, human; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; C033652:postsynaptic density proteins; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; C491075:Dlgh3 protein, mouse; D051528:Guanylate Kinases