title: Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration.
abstract: The precise mechanism by which mutant huntingtin elicits its toxicity remains unknown. However, synaptic alterations and increased susceptibility to neuronal death are known contributors to Huntington's disease (HD) symptomatology. While decreased metabolism has long been associated with HD, recent findings have surprisingly demonstrated reduced neuronal apoptosis in Caenorhabditis elegans and Drosophila models of HD by drugs that diminish ATP production. Interestingly, extracellular ATP has been recently reported to elicit neuronal death through stimulation of P2X7 receptors. These are ATP-gated cation channels known to modulate neurotransmitter release from neuronal presynaptic terminals and to regulate cytokine production and release from microglia. We hypothesized that alteration in P2X7-mediated calcium permeability may contribute to HD synaptic dysfunction and increased neuronal apoptosis. Using mouse and cellular models of HD, we demonstrate increased P2X7-receptor level and altered P2X7-mediated calcium permeability in somata and terminals of HD neurons. Furthermore, cultured neurons expressing mutant huntingtin showed increased susceptibility to apoptosis triggered by P2X7-receptor stimulation. Finally, in vivo administration of the P2X7-antagonist Brilliant Blue-G (BBG) to HD mice prevented neuronal apoptosis and attenuated body weight loss and motor-coordination deficits. These in vivo data strongly suggest that altered P2X7-receptor level and function contribute to HD pathogenesis and highlight the therapeutic potential of P2X7 receptor antagonists.
authors.affiliation: Centro de Biología Molecular Severo Ochoa, CSIC/UAM, Campus UAM de Cantoblanco, 28049 Madrid, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Díaz-Hernández
authors.forename: María
authors.initials: M
authors.lastname: Díez-Zaera
authors.forename: Jesús
authors.initials: J
authors.lastname: Sánchez-Nogueiro
authors.forename: Rosa
authors.initials: R
authors.lastname: Gómez-Villafuertes
authors.forename: Josep M
authors.initials: JM
authors.lastname: Canals
authors.forename: Jordi
authors.initials: J
authors.lastname: Alberch
authors.forename: María Teresa
authors.initials: MT
authors.lastname: Miras-Portugal
authors.forename: José J
authors.initials: JJ
authors.lastname: Lucas
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2 / Q000235:genetics / Q000378:metabolism*; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D045442:Rotarod Performance Test; D013569:Synapses / Q000378:metabolism
chemical_list: D018696:Neuroprotective Agents; C546468:P2RX7 protein, human; C546469:P2rx7 protein, mouse; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; C004692:coomassie Brilliant Blue; D002118:Calcium