Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A).
Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases and is associated with an interstitial chromosomal duplication of 17p12 (refs. 2,3). We have generated a model of CMT-1A by introducing extra copies of the responsible disease gene, Pmp22 (encoding the peripheral myelin protein of 22 kDa), into transgenic rats. Here, we used this model to test whether progesterone, a regulator of the myelin genes Pmp22 and myelin protein zero (Mpz) in cultured Schwann cells, can modulate the progressive neuropathy caused by moderate overexpression of Pmp22. Male transgenic rats (n = 84) were randomly assigned into three treatment groups: progesterone, progesterone antagonist (onapristone) and placebo control. 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.
Sereda
Michael W
MW
Max-Planck Institute of Experimental Medicine, Department of Neurogenetics, Hermann-Rein-Str. 3, D-37075 Göttingen, Germany.
Meyer zu Hörste
Gerd
G
Suter
Ueli
U
Uzma
Naureen
N
Nave
Klaus-Armin
KA
D000818:Animals; D030801:Animals, Genetically Modified; D002607:Charcot-Marie-Tooth Disease / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D006067:Gonanes / Q000627:therapeutic use; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D018993:Myelin P0 Protein / Q000235:genetics / Q000378:metabolism; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors
D006067:Gonanes; D006727:Hormone Antagonists; D018993:Myelin P0 Protein; D009185:Myelin Proteins; C073687:PMP22 protein, human; C489546:Pmp22 protein, rat; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D011374:Progesterone; C053238:onapristone