Phospholipid metabolism and membrane trafficking in the pathogenesis of Charcot-Marie-Tooth neuropathies

Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral neuropathy, generally characterized by progressive muscular atrophy and weakness with sensory loss, occurring in the distal extremities. The age of onset is usually between the first and the second decade of life. Among the different forms of CMT, CMT4B1 represents an autosomal recessive demyelinating neuropathy characterized by infantile onset with progressive symmetric distal and proximal weakness starting in the lower extremities, cranial nerve involvement in most of the cases, and focally folded myelin sheaths in the peripheral nerve. In 2000, funded by Telethon, I isolated the MTMR2 (Myotubularin-related 2) gene as responsible for CMT4B1. MTMR2 is a phosphatase acting on phospholipids, important second messengers within the cells that regulate a variety of functions including membrane trafficking. Myelin biogenesis during myelination is based on the correct delivery in time and space of membranes and therefore on membrane trafficking. During the last 10 years funded by Telethon we generated several in vivo and in vitro models of CMT4B1 and we demonstrated several interactors of MTMR2. However, the biological event that MTMR2 regulates within the cell is at present still unknown. To note that the phospholipid metabolism and how phospholipids regulate membrane trafficking during myelination is not known. Aim of this project is to unravel the biological function of MTMR2 in Schwann cells, the glial cells that produce myelin on the peripheral nervous system. Understanding how myelin biogenesis is regulated is relevant to favor axonal regeneration and remyelination not only for CMT4B1 but also for other disorders in which this process is impaired.