Molecular and Translational Neurology

Myelin Protein PMP22 in a transgenic rat model of Charcot-Marie-Tooth Disease (CMT1A) (in collaboration with Ueli Suter, Zurich)

Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy in humans. CMT1A is associated with a DNA duplication on chromosome 17p11.2-p12 that causes an increased gene dosage of peripheral myelin protein 22 (PMP22). Transgenic ("CMT") rats expressing additional copies of this gene show typical characteristics of the human disease such as muscle weakness, reduced nerve conduction velocity, peripheral demyelination and the typical "onion bulb formation".

Typical "onion bulb formation" in an ischiadicus nerve of a 6 month old “CMT rat”. Schwann cell hypertrophy leads to concentric Schwann cell extensions and excess basal laminae formed around a naked axon.

As in other mouse mutants carrying mutations in myelin genes of the peripheral nervous system (PNS), there is evidence in the "CMT rat" that PMP22 overexpression causes abnormal intracellular transport processes. With the help of the rat model, the molecular pathology of CMT1A can be elucidated. We are particularly interested in the ultrastructural analysis of pre-symptomatic Schwann cells in the early stages of the disease. We use biochemical methods to study the kinetics of myelination and intracellular sorting.

In homozygous PMP22 transgenic rats, Schwann cells do not form myelin and do not appear to progress beyond the "promyelin" stage, but they do express myelin genes that characterise mature Schwann cells. Increased PMP22 expression thus leads to a newly observed "uncoupling" of molecular and morphological parameters of Schwann cell differentiation.

Steroid hormones have been identified as coregulators of myelin gene expression. Progesterone influences myelination in Schwann cells and induces the expression of PMP22 in vitro and in vivo. To reduce the increased expression of PMP22, we have treated “CMT rats” with the progesterone antagonist onapristone. Treatment with the selective progesterone antagonist reduced PMP22 expression and led to an improvement in clinical phenotype. In contrast, daily progesterone treatment resulted in increased PMP22 and MPZ ("Myelin Protein Zero") expression in the sciatic nerve and a worsening of Schwann cell pathology with a more severe neuropathy.

In summary, in a proof of principle study we could show that the steroid receptor in myelinating Schwann cells is a promising pharmacological target for CMT1A therapy.

The “CMT rat” enables us to better understand the molecular and cellular causes of human CMT1A, e.g. to identify modifying genes and epigenetic factors and to evaluate new therapeutic strategies.

The CMT-NET network, which was funded by the German Federal Ministry of Education and Research (BMBF) from 2016 to 2020 and coordinated by Prof. Michael Sereda, brings together scientists and clinicians throughout Germany who are engaged in research and therapeutic options for CMT. The network focuses on translational research, i.e. the transfer of findings from animal models in the laboratory to patients in the clinic ("from bench to bedsite") and vice versa. Two studies on CMT1A have been conducted within the network, an observational study and a biomarker study. Publications on both studies are in preparation.

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