Subtle defects in paranodes of myelinated nerve fibers can cause significant physiological malfunction. We have investigated myelinated fibers in the peripheral nervous system (PNS) of the Trembler mouse, a model of CMT-1A neuropathy, for evidence of such defects. Ultrastructural analysis shows that the "transverse bands," which attach the myelin sheath to the axon at the paranodal axoglial junction, are grossly diminished in number in Trembler nerve fibers. Although paranodes often appear to be greatly elongated, it is only a short region immediately adjacent to the node of Ranvier that displays transverse bands. Where transverse bands are missing, the junctional gap widens, thus reducing resistance to short circuiting of nodal action currents during saltatory conduction and increasing the likelihood that axonal K(+) channels under the myelin sheath will be activated. In addition, we find evidence that structural domains in Trembler axons are incompletely differentiated, consistent with diminution in nodal Na channel density, which could further compromise conduction. Deficiency of transverse bands may also increase susceptibility to disruption of the paranodal junction and retraction of the myelin sheath. We conclude that Trembler PNS myelinated fibers display subtle defects in paranodal and nodal regions that could contribute significantly to conduction defects and increased risk of myelin detachment.
Keywords: CMT-1A; HNPP; myelin sheath; neuropathy; peripheral myelin protein; tremor mouse.
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