title: Evidence for impaired axonal regeneration in PMP22 duplication: studies in nerve xenografts.
abstract: Whether axonal regeneration in Charcot-Marie-Tooth (CMT) neuropathies is impaired has not been addressed in detail. Our studies in nude mice harboring xenografts from patients with different primary Schwann cell (SC) genetic defects suggested an intimate association between the onset of myelination and impairment in the growth capacity of nude mice axons engulfed by the mutant SCs. To assess the effects of peripheral myelin protein 22 (PMP22) gene duplication on the regeneration process, we conducted morphometric studies to generate temporal growth profiles of myelinated axons within the xenografts obtained from CMT1A patients and from healthy controls. Axon size distribution histograms in controls at different time intervals revealed that size differentiation of myelinated fibers within the grafts is established as early as 2 weeks, and that the temporal pattern of myelination of different sized axons has striking similarities to myelination during development. In PMP22 duplication grafts, the onset of myelination is delayed and the regeneration capacity of all fiber sizes is impaired. This defect, however, is most pronounced for the large diameter axons. In addition, significant large fiber loss occurred after 12 weeks with a concomitant new cycle of regeneration of small size axons. These studies show that the PMP22 duplication in SCs have profound effects on the regeneration process, which might be a contributing factor to preferential distal axonal loss.
authors.affiliation: Department of Neurology, Neuromuscular Disease Center, The Ohio State University, Means Hall 4th Floor, 1654 Upham Drive, Columbus, OH 43210, USA. sahenk.1@osu.edu
authors.forename: Zarife
authors.initials: Z
authors.lastname: Sahenk
authors.forename: Carmen
authors.initials: C
authors.lastname: Serrano-Munuera
authors.forename: Lei
authors.initials: L
authors.lastname: Chen
authors.forename: Inga
authors.initials: I
authors.lastname: Kakabadze
authors.forename: Haikady N
authors.initials: HN
authors.lastname: Najagara
mesh_terms: D000328:Adult; D000818:Animals; D001369:Axons / Q000145:classification / Q000502:physiology / Q000637:transplantation* / Q000648:ultrastructure; D016022:Case-Control Studies; D002452:Cell Count; D048429:Cell Size / Q000502:physiology; D002607:Charcot-Marie-Tooth Disease / Q000503:physiopathology*; D020440:Gene Duplication; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008854:Microscopy, Electron; D008875:Middle Aged; D009185:Myelin Proteins / Q000235:genetics* / Q000378:metabolism; D009413:Nerve Fibers, Myelinated / Q000378:metabolism / Q000637:transplantation* / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000502:physiology*; D012583:Schwann Cells / Q000648:ultrastructure; D013997:Time Factors; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D009185:Myelin Proteins; C073687:PMP22 protein, human; C489545:Pmp22 protein, mouse