PDE4D inhibition to improve peripheral myelination, Schwann cell differentiation and motor function in Charcot-Marie-Tooth disease type 1A

Abstract

Charcot-Marie-Tooth disease type 1A (CMT1A) is an inherited neuropathy of the peripheral nervous system. Symptoms include distal muscle weakness and atrophy, as well as sensory loss. Currently, no therapies for CMT1A are available. CMT1A is characterized by Schwann cell (SC) dedifferentiation and demyelination. The differentiation of SCs to the myelinating phenotype and the subsequent myelination process are positively regulated by cAMP. Therefore, we hypothesized that elevating intracellular cAMP levels by inhibiting PDE4D, a main cAMP-hydrolyzing enzyme in SCs, can stimulate SC differentiation, myelination and subsequent functional repair in the C3-PMP22 mouse model. Primary SCs were treated with 3 different inhibitors and their differentiation was investigated by assessing gene expression of several SC differentiation markers by qPCR, as well as the protein levels of several markers using immunocytochemistry. These experiments were inconclusive. Secondly, the therapeutic potential of PDE4D inhibitor GEBR-32a was evaluated in vivo. Mice were injected with 0.3 mg/kg GEBR-32a twice per day for 7 weeks, and motor function was assessed using several behavioral assays. We found that GEBR-32a treatment significantly improves motor function in C3-PMP22 mice. Furthermore, electrophysiological recordings showed a significant increase in nerve conduction speed. In conclusion, these findings indicate a promising therapeutic potential of PDE4D inhibition in CMT1A, although the exact molecular mechanisms need to be evaluated in vitro.