AN IN VITRO MODEL OF MYELIN PROTEIN ZERO MUTATIONS IN SCHWANN CELLS: FROM PATHOGENESIS TO THERAPY

Myelin protein zero (MPZ) mutations cause the Charcot Marie Tooth 1B (CMT1B) neuropathy. This projects aims to develop an experimental model in Schwann cells, the cells responsible for the synthesis of myelin in the peripheral nervous system, in order to identify the pathogenic mechanisms of MPZ mutations and to try new therapeutic agents. So far, the pathogenic mechanisms of MPZ mutations have been studied in cell lines not expressing MPZ, making difficult to extend the conclusions to human patients. We are planning to culture Schwann cells deriving from the heterozygous MPZ knock out animal, therefore characterized by a single allele coding for MPZ. These cells may be infected with viral vectors genetically modified in order to express MPZ mutations. This would create a model very similar to the human condition where the same Schwann cell expresses both alleles: the normal and the mutated one. We will use this model to test two interesting molecules: curcumin and salubrinal. The first was already demonstrated to be beneficial for MPZ mutations in a cell line normally not expressing MPZ. It is therefore necessary to test this molecule in Schwann cells to prove that it is not toxical and to evaluate its efficacy. The second molecule is salubrinal which has been demonstrated to mitigate the toxic effect of mutated proteins. In conclusion, a Schwann cell based in vitro model, may offer the advantage to screen promising molecules, a preliminary step to any further therapeutic trial in human patients.