Investigating Cx32 hemichannel dysfunction in Schwann cells: a potential therapeutic target for the X-linked form of Charcot-Marie-Tooth.

Connexin 32 (Cx32) is a fundamental protein in the peripheral nervous system as its mutations cause the X-linked form of Charcot–Marie–Tooth disease (CMT1X), a demyelinating motor and sensory neuropathy without cure. Despite the availability of a sizable number of studies focusing on normal and mutated Cx32 channel properties, the molecular pathogenesis of CMT1X has not yet been elucidated. Our laboratory has been active in connexin research for several years and has developed, in collaboration with Italian and foreign partners, biophysical tools and methodologies that promise to provide crucial insight into the physiology and pathology of peripheral nerves, as well as clues for the development of pharmacological treatments that could stop CMT1X progression or alleviate the suffering of patients. Specific aims of this project are 1) the identification of extracellular messenger molecules, such as ATP, whose signaling is pathologically altered by Cx32 mutations and 2) the development of a new model based on Schwann cells in culture to reproduce the function of Cx32 channels in the myelin of the human peripheral nervous system. This is not a merely academic exercise; it will contribute to the search for a cure once we understand what it is that goes wrong when connexins fail to perform.