title: Antiprogesterone therapy uncouples axonal loss from demyelination in a transgenic rat model of CMT1A neuropathy.
abstract: OBJECTIVE
  Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy, and a duplication of the Pmp22 gene causes the most frequent subform CMT1A. Using a transgenic rat model of CMT1A, we tested the hypothesis that long-term treatment with anti-progesterone (Onapristone) reduces Pmp22 overexpression and improves CMT disease phenotype of older animals, thereby extending a previous proof-of-concept observation in a more clinically relevant setting.
  
  
  METHODS
  We applied placebo-controlled progesterone-antagonist therapy to CMT rats for 5 months and performed grip-strength analysis to assess the motor phenotype. Quantitative Pmp22 RT-PCR and complete histological analysis of peripheral nerves and skin biopsies were performed.
  
  
  RESULTS
  Anti-progesterone therapy significantly increased muscle strength and muscle mass of CMT rats and reduced the performance difference to wildtype rats by about 50%. Physical improvements can be explained by the prevention of axon loss. Surprisingly, the effects of anti-progesterone were not reflected by improved myelin sheath thickness. Electrophysiology confirmed unaltered NCV, but less reduced CMAP recordings in the treatment group. Moreover, the reduction of Pmp22 mRNA, as quantified in cutaneous nerves, correlated with the clinical phenotype at later stages.
  
  
  CONCLUSIONS
  Progesterone-antagonist long-term therapy reduces [corrected] Pmp22 overexpression to a degree at which the axonal support function of Schwann cells is better maintained than myelination. This suggests that axonal loss in CMT1A is not caused by demyelination, but rather by a Schwann cell defect that has been partially uncoupled by anti-progesterone treatment. Pmp22 expression analysis in skin may provide a prognostic marker for disease severity and for monitoring future clinical trials.
authors.affiliation: Department of Neurogenetics, Max-Planck-Institute of Experimental Medicine, University of Göttingen, Göttingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Meyer zu Horste
authors.forename: Thomas
authors.initials: T
authors.lastname: Prukop
authors.forename: David
authors.initials: D
authors.lastname: Liebetanz
authors.forename: Wiebke
authors.initials: W
authors.lastname: Mobius
authors.forename: Klaus-Armin
authors.initials: KA
authors.lastname: Nave
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000367:Age Factors; D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D001369:Axons / Q000187:drug effects* / Q000502:physiology / Q000648:ultrastructure; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000188:drug therapy* / Q000473:pathology*; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000209:etiology / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006067:Gonanes / Q000627:therapeutic use*; D006727:Hormone Antagonists / Q000627:therapeutic use*; D018482:Muscle, Skeletal / Q000187:drug effects / Q000503:physiopathology; D009185:Myelin Proteins / Q000235:genetics / Q000378:metabolism; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology
chemical_list: D006067:Gonanes; D006727:Hormone Antagonists; D009185:Myelin Proteins; C489546:Pmp22 protein, rat; C053238:onapristone