title: Evidence for macrophage-mediated myelin disruption in an animal model for Charcot-Marie-Tooth neuropathy type 1A.
abstract: Charcot-Marie-Tooth neuropathy type 1A (CMT 1 A) is the most common inherited neuropathy in humans and is mostly caused by a 1.5-Mb tandem duplication of chromosome 17 comprising the gene for the peripheral myelin protein 22-kDa (PMP 22). Although there are numerous studies on the functional role of PMP 22, the mechanisms of myelin degeneration under PMP 22-overexpression conditions have not yet been fully understood. We have shown previously that in mouse mutants hetero- or homozygously deficient for two other myelin components, P0 and C x 32, respectively, immune cells contribute to the demyelinating neuropathy. To test this possibility for PMP 22 overexpression, we investigated a putative mouse model for CMT 1 A, i.e., the mouse strain C 6 1 mildly overexpressing human PMP 22 in peripheral nerves. Electron microscopic and electrophysiologic investigations revealed that this mouse strain develops pathologic features similar to those found in CMT 1 A patients. A novel finding, however, was the upregulation of CD8- and F4/80-positive lymphocytes and macrophages, respectively, in peripheral nerves. The observation that macrophages enter endoneurial tubes of the mutants and obviously phagocytose morphologically normal myelin strongly suggests that the myelin degeneration is mediated at least partially by these phagocytic cells. By gene array technology and quantitative RT-PCR of peripheral nerve homogenates from PMP 22 mutants, monocyte chemoattractant protein-1 (MCP-1; cc l2) could be identified as a putative factor to attract or activate macrophages that attack myelin sheaths in this model of CMT 1 A.
authors.affiliation: Developmental Neurobiology, Department of Neurology, University of Würzburg, Würzburg, Germany.
authors.forename: Igor
authors.initials: I
authors.lastname: Kobsar
authors.forename: Kerstin
authors.initials: K
authors.lastname: Hasenpusch-Theil
authors.forename: Carsten
authors.initials: C
authors.lastname: Wessig
authors.forename: Hans Werner
authors.initials: HW
authors.lastname: Müller
authors.forename: Rudolf
authors.initials: R
authors.lastname: Martini
mesh_terms: D000375:Aging / Q000502:physiology; D000818:Animals; D001369:Axons / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology; D002607:Charcot-Marie-Tooth Disease / Q000473:pathology*; D018932:Chemokine CCL2 / Q000096:biosynthesis; D003711:Demyelinating Diseases / Q000473:pathology; D004594:Electrophysiology; D006801:Humans; D007150:Immunohistochemistry; D008264:Macrophages / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009185:Myelin Proteins / Q000235:genetics; D009186:Myelin Sheath / Q000473:pathology*; D010525:Peripheral Nerves / Q000378:metabolism / Q000473:pathology; D012313:RNA / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012584:Sciatic Nerve / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D009185:Myelin Proteins; C489545:Pmp22 protein, mouse; D012313:RNA