Abstract
Charcot‐Marie‐Tooth neuropathy type 1A (CMT1A) 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 (PMP22). Although there are numerous studies on the functional role of PMP22, the mechanisms of myelin degeneration under PMP22‐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 Cx32, respectively, immune cells contribute to the demyelinating neuropathy. To test this possibility for PMP22 overexpression, we investigated a putative mouse model for CMT1A, i.e., the mouse strain C61 mildly overexpressing human PMP22 in peripheral nerves. Electron microscopic and electrophysiologic investigations revealed that this mouse strain develops pathologic features similar to those found in CMT1A 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 PMP22 mutants, monocyte chemoattractant protein‐1 (MCP‐1; ccl2) could be identified as a putative factor to attract or activate macrophages that attack myelin sheaths in this model of CMT1A. © 2005 Wiley‐Liss, Inc.