Peripheral nerve extracellular matrix remodeling in Charcot-Marie- Tooth type I disease.

Charcot-Marie-Tooth type 1 disease (CMT1) is a group of inherited demyelinating neuropathies caused by mutations in genes expressed by myelinating Schwann cells. Rather than demyelination per se, alterations of Schwann cell-axon interactions have been suggested as the main cause of motor-sensory impairment in CMT1 patients. In an attempt to identify molecules that may be involved in such altered interactions, the extracellular matrix (ECM) remodeling occurring in CMT1 sural nerves was studied. For comparison, both normal sural nerves and sural nerves affected by neuropathies of different origin were used. The study was performed by immunohistochemical analysis using antibodies against collagen types I, III, IV, V, and VI and the glycoproteins fibronectin, laminin, vitronectin and tenascin. Up-regulation of collagens, fibronectin and laminin was commonly found in nerve biopsy specimens from patients affected by CMT1 and control diseases, but higher levels of overexpression were usually observed in CMT1 cases. On the other hand, vitronectin and tenascin appeared preferentially induced in CMT1 compared to other pathologies investigated here. Vitronectin, whose expression in normal nerves was limited to perineurial layers and to the walls of epineurial and endoneurial vessels, became strongly and diffusely expressed in the endoneurium in most CMT1 biopsy specimens. The expression of tenascin, confined to the perineurium, to vessel walls and to the nodes of Ranvier in normal nerves, was displaced and extended along the internodes of several nerve fibers in the majority of CMT1 nerves. Thus, compared with our pathological controls CMT1 seemed to determine the most extensive remodeling of peripheral nerve ECM.