Pharmacological modulation of myelin synthesis and cytoskeletal remodeling as a therapeutic strategy for CMT4B neuropathies with aberrant myelin.

Charcot-Marie-Tooth (CMT) neuropathies represent a broad group of inherited disorders with a prevalence of 1 on 2500 individuals. CMTs are generally characterized by progressive muscular atrophy and weakness, with an age at onset usually comprised between the first and the second decade of life. Among CMT neuropathies, CMT4B1 is a very severe demyelinating neuropathy with childhood onset, characterized by myelin outfoldings, redundant loops of myelin in the nerve that degenerate causing axonal problems. This form of aberrant myelin is also a pathological feature of other forms of demyelinating CMT, such as CMT4B2, B3, CMT4C and CMT4H. Our laboratory demonstrated that loss of MTMR2 (Myotubularin-related 2) phosphatase is the cause of the disease. MTMR2 dephosphorylates phospholipids, important regulators of membrane trafficking, which is a key process in Schwann cells, the glial cells forming myelin in the peripheral nervous system. We also generated in vitro and in vivo models of CMT4B1, which have been instrumental over the years to study the pathophysiology of this neuropathy. By investigating why loss of MTMR2 in Schwann cells provokes aberrant myelin, we identified a novel mechanism by which MTMR2 and its lipid substrate coordinate cytoskeleton dynamics and membrane growth within myelin-forming cells. In this project, we will test whether pharmacological modulation of these pathways can represent an effective strategy for the therapy of CMT4B1 with myelin outfoldings. Of note, we will also validate this approach in a CMT4B2 neuropathy model with aberrant myelin.