Abnormal Schwann cell-axon interactions in CMT neuropathies. The effects of mutant Schwann cells on the axonal cytoskeleton and regeneration-associated myelination.

Preferential distal axonal loss is a common feature of Charcot-Marie-Tooth (CMT) hereditary neuropathies. The general hypothesis tested here is that the axonal loss in these disorders is due to perturbed Schwann cell-axon interactions resulting from primary Schwann genetic defects. The nerve xenograft model was used to study the local influence of mutant Schwann cells derived from patients on axonal properties and the regeneration-associated myelination process. Sural nerve segments from individuals with PMP22 duplications or deletions and point mutations, as well as Cx32 point mutations were grafted into cut ends of the sciatic nerve of nude mice and studied at different time intervals after grafting. CMT1A and CMTX xenografts examined at 16 weeks show that the nude mouse axons within the proximal part of grafts demonstrate a significant increase in axonal area with an increase in the neurofilament and membranous organelle density compared to distal graft and distal host segments. A preferential distal axonal loss associated with a perpetual axonal atrophy, degeneration, and axonal sprouting was observed over time with increasing frequency at 8 to 16 weeks. A distal summation of the pathology, as evidenced by a greater amount of fiber loss in the distal graft segments, was present similar to that observed in patients. These alterations were seen to a lesser extent in PMP22 deletion or point mutation xenografts and were not observed in controls. Collectively, these findings show that Schwann cells bearing the PMP22 or Cx32 genetic defects cause major perturbations in Schwann cell-axon interactions emphasizing the role of axonal component in the pathogenesis of hereditary neuropathies.