Role of purinergic receptors in myelination: therapeutic implications for treatment of the peripheral neurophaty Charcot-Marie-Tooth 1A

In our study we will test therapeutical strategies for Charcot-Marie-Tooth disease type 1A (CMT1A). CMT, with a prevalence of 1 case in 2500, is the most common type of genetic neurological disorder and in the majority of cases (CMT1A) it is associated with a duplication of the peripheral myelin protein PMP22 gene. Clinical features include distal, symmetrical lower extremity weakness, wasting of foot and leg muscles and increasing walking difficulty. Slow nerve conduction velocity is caused by peripheral demyelination. PMP22 overexpression causes CMT1A: although the genetic defect is well known, the molecular mechanisms underlying CMT1A need to be clarified and no pharmacological treatment is currently available. Based on our finding that PMP22 overexpression also determines overexpression of the purinergic receptor P2X7 in CMT1A Schwann cells (SC), causing a derangement of the intracellular calcium homeostasis, we are planning to explore therapeutic approaches aimed at correcting these biochemical alterations in CMT1A SC. Specifically, in this project we will test in the rat model of CMT1A the "in vivo" efficacy of a P2X7 antagonist, which restores the normal intracellular Ca2+ levels and myelination in "in vitro" cultures from CMT1A rats. In addition, we found that in CMT1A SC, the level of the second messenger cAMP is decreased compared to wild type SC. cAMP plays a fundamental role in orchestrating SC differentiation and myelination. Thus, we will investigate whether the concomitant action on P2X7 and on another member of the purinergic receptor family, P2Y11, whose activation is coupled to cAMP increase, could be of further advantage in improving myelination. To this end, we will use a new compound we identified as uniquely endowed with the property of being both a P2X7 antagonist and a P2Y11 agonist. The use of this compound could represent the first treatment aimed at correcting a pathogenetic mechanism underlying demyelination in CMT1A.