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Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A)

Abstract

Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. The predominant subtype, CMT-1A, accounts for more than 50% of all cases1 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 rats4. 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.

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Figure 1: CMT rats show interindividual variation in Pmp22 expression, muscle atrophy and clinical phenotype.
Figure 2: Progesterone modulates myelin gene expression in CMT rats.
Figure 3: Histopathology of progesterone- and onapristone-treated CMT rats.
Figure 4: Progesterone and onapristone modulate the disease phenotype of CMT rats.

References

  1. 1

    Boerkoel, C.F. et al. Charcot-Marie-Tooth disease and related neuropathies: mutation distribution and genotype-phenotype correlation. Ann. Neurol. 51, 190–201 (2002).

    CAS  Article  Google Scholar 

  2. 2

    Lupski, J.R. et al. DNA duplication associated with Charcot-Marie-Tooth disease type 1A. Cell 66, 219–232 (1991).

    CAS  Article  Google Scholar 

  3. 3

    Raeymaekers, P. et al. Duplication in chromosome 17p11.2 in Charcot-Marie-Tooth neuropathy type 1a (CMT 1a). The HMSN Collaborative Research Group. Neuromuscul. Disord. 1, 93–97 (1991).

    CAS  Article  Google Scholar 

  4. 4

    Sereda, M. et al. A transgenic rat model of Charcot-Marie-Tooth disease. Neuron 16, 1049–1060 (1996).

    CAS  Article  Google Scholar 

  5. 5

    Berger, P., Young, P. & Suter, U. Molecular cell biology of Charcot-Marie-Tooth disease. Neurogenetics 4, 1–15 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Thomas, P.K. et al. The phenotypic manifestations of chromosome 17p11.2 duplication. Brain 120, 465–478 (1997).

    Article  Google Scholar 

  7. 7

    Garcia, C.A. et al. Clinical variability in two pairs of identical twins with the Charcot- Marie-Tooth disease type 1A duplication. Neurology 45, 2090–2093 (1995).

    CAS  Article  Google Scholar 

  8. 8

    Jung-Testas, I. et al. Progesterone as a neurosteroid: synthesis and actions in rat glial cells. J. Steroid Biochem. Mol. Biol. 69, 97–107 (1999).

    CAS  Article  Google Scholar 

  9. 9

    Koenig, H.L. et al. Progesterone synthesis and myelin formation by Schwann cells. Science 268, 1500–1503 (1995).

    CAS  Article  Google Scholar 

  10. 10

    Lin, R.J., Kao, H.Y., Ordentlich, P. & Evans, R.M. The transcriptional basis of steroid physiology. Cold Spring Harb. Symp. Quant. Biol. 63, 577–585 (1998).

    CAS  Article  Google Scholar 

  11. 11

    Desarnaud, F. et al. Progesterone stimulates the activity of the promoters of peripheral myelin protein-22 and protein zero genes in Schwann cells. J. Neurochem. 71, 1765–1768 (1998).

    CAS  Article  Google Scholar 

  12. 12

    Melcangi, R.C. et al. Progesterone derivatives are able to influence peripheral myelin protein 22 and P0 gene expression: possible mechanisms of action. J. Neurosci. Res. 56, 349–357 (1999).

    CAS  Article  Google Scholar 

  13. 13

    Schumacher, M. et al. Progesterone synthesis and myelin formation in peripheral nerves. Brain Res. Brain Res. Rev. 37, 343–359 (2001).

    CAS  Article  Google Scholar 

  14. 14

    Michna, H., Fritzemeier, K.H., Parczyk, K., Nishino, Y. & Schneider, M.R. Antiprogestin-progesterone interactions. Cancer Treat Res. 83, 191–212 (1996).

    CAS  Article  Google Scholar 

  15. 15

    Graham, J.D. & Clarke, C.L. Expression and transcriptional activity of progesterone receptor A and progesterone receptor B in mammalian cells. Breast Cancer Res. 4, 187–190 (2002).

    CAS  Article  Google Scholar 

  16. 16

    Edwards, D.P. et al. Progesterone receptor and the mechanism of action of progesterone antagonists. J. Steroid Biochem. Mol. Biol. 53, 449–458 (1995).

    CAS  Article  Google Scholar 

  17. 17

    Butcher, R.L., Collins, W.E. & Fugo, N.W. Plasma concentration of LH, FSH, prolactin, progesterone and estradiol- 17beta throughout the 4-day estrous cycle of the rat. Endocrinology 94, 1704–1708 (1974).

    CAS  Article  Google Scholar 

  18. 18

    Suter, U. et al. Regulation of tissue-specific expression of alternative peripheral myelin protein-22 (PMP22) gene transcripts by two promoters. J. Biol. Chem. 269, 25795–25808 (1994).

    CAS  PubMed  Google Scholar 

  19. 19

    Magyar, J.P. et al. Impaired differentiation of Schwann cells in transgenic mice with increased PMP22 gene dosage. J. Neurosci. 16, 5351–5360 (1996).

    CAS  Article  Google Scholar 

  20. 20

    Huxley, C. et al. Construction of a mouse model of Charcot-Marie-Tooth disease type 1A by pronuclear injection of human YAC DNA. Hum. Mol. Genet. 5, 563–569 (1996).

    CAS  Article  Google Scholar 

  21. 21

    Niemann, S., Sereda, M.W., Suter, U., Griffiths, I.R. & Nave, K.A. Uncoupling of myelin assembly and schwann cell differentiation by transgenic overexpression of peripheral myelin protein 22. J. Neurosci. 20, 4120–4128 (2000).

    CAS  Article  Google Scholar 

  22. 22

    Perea, J. et al. Induced myelination and demyelination in a conditional mouse model of Charcot-Marie-Tooth disease type 1A. Hum. Mol. Genet. 10, 1007–1018 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Guennoun, R. et al. Progesterone stimulates Krox-20 gene expression in Schwann cells. Brain Res. Mol. Brain Res. 90, 75–82 (2001).

    CAS  Article  Google Scholar 

  24. 24

    Pollock, M., Nukada, H. & Kritchevsky, M. Exacerbation of Charcot-Marie-tooth disease in pregnancy. Neurology 32, 1311–1314 (1982).

    CAS  Article  Google Scholar 

  25. 25

    Rudnik-Schoneborn, S., Rohrig, D., Nicholson, G. & Zerres, K. Pregnancy and delivery in Charcot-Marie-Tooth disease type 1. Neurology 43, 2011–2016 (1993).

    CAS  Article  Google Scholar 

  26. 26

    Robertson, J.F., Willsher, P.C., Winterbottom, L., Blamey, R.W. & Thorpe, S. Onapristone, a progesterone receptor antagonist, as first-line therapy in primary breast cancer. Eur. J. Cancer 35, 214–218 (1999).

    CAS  Article  Google Scholar 

  27. 27

    Gopalkrishnan, K., Katkam, R.R., Sachdeva, G., Kholkute, S.D., Padwal, V. & Puri, C.P. Effects of an antiprogestin onapristone on the endometrium of bonnet monkeys: morphometric and ultrastructural studies. Biol. Reprod. 68, 1959–1967 (2003).

    CAS  Article  Google Scholar 

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Acknowledgements

We thank E. Nicksch, U. Bode and C. Stünkel for technical help; M.R. Schneider (Schering) for providing us with onapristone; C. Scheidt-Nave for statistical advice; J.R. Lupski for helpful comments on the manuscript; and members of the Nave lab for discussion. This work was supported by the Max-Planck Society and by grants from the European Union (to K.A.N.). U.S. was supported by the Swiss National Science Foundation and by the National Center for Competence in Research “Neural Plasticity and Repair”. M.W.S. was supported in part by the Departments of Clinical Neurophysiology and Neurology at the University of Göttingen.

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Correspondence to Klaus-Armin Nave.

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Sereda, M., Meyer zu Hörste, G., Suter, U. et al. Therapeutic administration of progesterone antagonist in a model of Charcot-Marie-Tooth disease (CMT-1A). Nat Med 9, 1533–1537 (2003). https://doi.org/10.1038/nm957

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