Anales RANF

P.34 REGULATION OF THE UBIQUITIN-PROTEASOME SYSTEM BY P2X7 RECEPTOR, RELEVANCE ON NEUROLOGICAL PATHOLOGIES. Carolina Bianchi 1,2 , Caterina DiLauro 1,2 , Laura de-Diego 1,2,3 , Mercedes Ramirez- Escudero 1 , Carlos Martinez-Frailes 1,2 , Alvaro Sebastian-Serrano 1,2,4 and Miguel Diaz- Hernandez 1,2 1 Department of Biochemistry and Molecular Biology, Veterinary School, Complutense University of Madrid, Madrid, Spain; 2 Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain; 3 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland; 4 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas, Instituto de Salud Carlos III, Madrid, Spain. The ubiquitin-proteasome-system (UPS) is the major intracellular pathway leading to the degradation of misfolded, unassembled, or damaged soluble proteins that could otherwise form potentially toxic aggregates. Dysregulation of UPS has been proposed as a common mechanism underlying several neurological pathologies, including Alzheimer’s Disease (AD) and epilepsy. Taking into account that extracellular nucleotides through their selective purinergic P2Y2 receptor (P2Y2R) modulates the UPS activity, we wonder if the purinergic P2X7 receptor (P2X7R) is also involved in the UPS impairment associated with the neuroinflammation process . Using murine neuroblastoma cell line N2a, we found that the stimulation of native P2X7R by its selective P2X7 agonist 2 ′(3′) -O-(4-benzoylbenzoyl) ATP (BzATP) induced a significant reduction in two of three peptidase proteasome activities, Chymotrypsin (CT) and Postglutamyl (PG) activities. Similar results were obtained using in vivo approaches, finding that intracerebroventricular administration of BzATP to wild type mice caused a significant reduction on both hippocampal proteasomal activities, but not in P2X7R Knock-Out mice (P2X7R KO). Accordantly, specific P2X7R antagonist (A438073) increased the chymotrypsin activity in the hippocampus of wild-type mice. Furthermore, additional analysis revealed that P2X7R KO mice present a decrease on polyubiquitinated conjugates, whereas P2X7R Overexpression mice (P2X7R OX) shown an increase in the accumulation of those proteins 24 hours after status epilepticus triggered by an intra-amygdala administration of kainic acid (KA). Altogether, our results suggest that P2X7R may be a novel selective target to regulate the proteasomal alterations related to neurological pathologies .