Mechanisms of axonal degeneration in late onset CMT1B neuropathies: molecular pathways and therapeutic approaches

Charcot Marie Tooth (CMT) neuropathies are a group of rare disorders of the peripheral nervous system that affects the development and the integrity of myelin, the fatty sheath surrounding the nerves. Although many disease genes have been identified for neuropathies, how disease is caused is poorly understood, and there is no effective treatment. For example, the mechanisms underlying axonal degeneration (the basis of patients’ disability) in demyelinating CMT are still unknown. Some forms of CMT may be caused by mutations in the “myelin-protein-zero” encoding gene (MPZ). Recent studies suggest that MPZ mutations causing axonal CMT may alter the myelin-axon connections. In order to understand these connections, and to envisage a therapeutic treatment, we study mice containing the mutant gene, that we have shown produce excellent model of the disease. In these mice we have identified a potential toxic mechanism, and we now propose to further analyse this pathway and to investigate how its genetic and pharmacological modulation may improve the disease outcome with the final goal to treat hereditary neuropathies. In parallel, we will evaluate a large CMT population carrying the same MPZ mutations causing axonal forms of CMT, to determine the natural course of the neuropathies along two years. The disease severity will be measured with clinical scales. The studies in patients will allow us to be prepared for future clinical trials.