gms | German Medical Science

Introduction: A progressive loss of axons determines the clinical phenotype of chronic demyelinating peripheral neuropathies, such as the incurable Charcot Marie Tooth disease type 1A (CMT1A). Even though most affected patients only seek medical advice in young adulthood, a moderate walking disability and electrophysiological abnormalities are usually already present in childhood.

Objectives: We here aimed to investigate the pathological and molecular changes of peripheral nerves during postnatal development in order to understand the clinical symptoms of children in CMT1A. We hypothesized that modulating peripheral nerve development may alter the disease course of CMT1A on the long-term.

Material and methods: We therefore took advantage of different rodent models for CMT1A, which mimic closely the human disease. We employed light and electron microscopy, molecular biology as well as additional transgenic and mutant mouse models to analyse peripheral nerve development and disease pathogenesis in CMT1A.

Results: We found that Schwann cells in rodent models of CMT1A mount a cell autonomous dysdifferentiation program already during early postnatal myelination which is sustained throughout life. Importantly, dysdifferentiation is associated with a disturbed balance of the PI3K and ERK signaling pathway.

We demonstrate that the soluble type I isoform of Neuregulin1 drives diseased Schwann cells towards differentiation via modulation of PI3K signaling. In a preclinical therapeutic trial, a short term Neuregulin1 treatment early postnatally ameliorated the perturbed postnatal peripheral nerve development and restored nerve function in CMT1A rodent models into adulthood.

Conclusion: These findings support a model in which myelination independent Schwann cell differentiation is crucial for the long-term maintenance of axonal support. Targeting Schwann cell differentiation may hence constitute a promising, common therapeutic approach in peripheral nerve disorders.