Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration

• Published in: The FASEB journal Vol. 23; no. 6; pp. 1893 - 1906
• Main Authors: Díaz-Hernández, Miguel, Díez-Zaera, María, Sánchez-Nogueiro, Jesús, Gómez-Villafuertes, Rosa, Canals, Josep M, Alberch, Jordi, Miras-Portugal, María Teresa, Lucas, José J
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01.06.2009
• Subjects: Animals; Apoptosis - physiology; Calcium - metabolism; Cell Survival - physiology; Cells, Cultured; Disease Models, Animal; Humans; Huntington Disease - drug therapy; Huntington Disease - metabolism; Huntington Disease - pathology; Mice; Mice, Knockout; Neurons - cytology; Neurons - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Purinergic P2 Receptor Antagonists; Receptors, Purinergic P2 - genetics; Receptors, Purinergic P2 - metabolism; Receptors, Purinergic P2X7; Rosaniline Dyes - metabolism; Rosaniline Dyes - pharmacology; Rosaniline Dyes - therapeutic use; Rotarod Performance Test; Synapses - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.08-122275

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.--Díaz-Hernández, M., Díez-Zaera, M., Sánchez-Nogueiro, J., Gómez-Villafuertes, R., Canals, J. M., Alberch, J., Miras-Portugal, M. T., Lucas, J. J. Altered P2X7-receptor level and function in mouse models of Huntington's disease and therapeutic efficacy of antagonist administration.