Myelin Protein PMP22 in a transgenic rat model of Charcot-Marie-Tooth Disease (CMT1A)
Michael W. Sereda, Gerd Meyer zu Hörste, Naureen Uzma, Thomas Prukop (In collaboration with Ueli Suter, Zurich)
Prof. Dr. Michael Sereda
Tetraspan myelin proteins play an important role in CNS and PNS myelination. We have generated a transgenic rat model of the most frequent human neuropathy, Charcot-Marie-Tooth disease type 1A (CMT1A). This disease is associated with a partial duplication of chromosome 17 and we have proven experimentally that the underlying cause is overexpression of the PMP22 gene. Transgenic rats expressing additional copies of this gene share characteristic clinical features of the human disease, including muscle weakness, reduced nerve conduction velocities, and marked Schwann cell hypertrophy resulting in onion bulb formation.
Typical onion-bulb formation of a 6 month-old CMT-rat showing concentric layers of Schwann cell processes and redundant basal laminae around a naked axon.
PMP22 overexpression may result in defects of intracellular protein trafficking. The rat model allows to adress the molecular pathology of CMT1A in more detail than previously possible with human biopsy material. We are specifically interested in the ultrastructural analysis of presymptomatic Schwann cells at early disease stages. Moreover, we are applying the tools of biochemistry and radioactive labeling of protein synthesis (ex vivo) to study the kinetics of myelination and intracellular protein sorting.
When bred to homozygosity, PMP22 transgenic rats completely fail to elaborate myelin and Schwann cells appear to be developmentally arrested at the "promyelin"stage. However, all myelin genes which mark the mature Schwann cell phenotype are normally expressed. Thus, a several-fold PMP22 overexpression causes a novel uncoupling of the molecular and morphological parameters of Schwann cell differentiation.
Steroid hormones have recently been identified as coregulators of Schwann cell function and peripheral myelination. Progesterone increases the expression of PMP22 in Schwann cell cultures and in the peripheral nervous system in vivo. In an attempt to lower PMP22 overexpression, we applied the progesterone receptor antagonist Onapristone to CMT-rats. Daily administration of progesterone elevated the steady-state levels of Pmp22 and Mpz mRNA in the sciatic nerve, resulting in enhanced Schwann cell pathology and a more progressive clinical neuropathy. In contrast, administration of the selective progesterone receptor antagonist reduced overexpression of Pmp22 and improved the CMT phenotype, without obvious side effects, in wild-type or transgenic rats. Taken together, these data provide proof of principle that the progesterone receptor of myelin-forming Schwann cells is a promising pharmacological target for therapy of CMT-1A. We are currently planning follow-up studies to pave the way to clinical application.
In summary, the CMT rat allows a better understanding of the cellular disease mechanism operating in human CMT1A, and should be helpful in the analysis of modifier genes, epigenetic factors, and in the evaluation of experimental treatment strategies.
Prof. Dr. Michael Sereda, MD
Department of Neurogenetics
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