Degeneration and Regeneration of Peripheral Motor Axons Is Impaired in Mice Heterozygously Deficient for the Myelin Protein P0 Gene (IN1-2.001)

Abstract

Objective: The aim of this study was to compare degeneration and regeneration of peripheral motor axons in early symptomatic P 0 +/- and age matched WT. Background Mice with a heterozyogous knock-out of the myelin protein P 0 gene (P 0 +/-) are models of Charcot-Marie-Tooth disease. The mice are indistinguishable from wild-types (WT) at birth; however, from about 7 months of age, they develop a slowly progressing demyelinating neuropathy. Although conduction slowing is known to be associated with a reduction of compound muscle action potential (CMAP) amplitude, the relationship between demyelination and axonal loss remains poorly understood. Design/Methods: Right sciatic nerves were lesioned at the thigh. Changes of the tibial nerve at ankle were investigated by electrophysiological, histological and molecular methods. In vivo motor nerve electrophysiology was carried out by conventional conduction studies and axon excitability studies using threshold tracking. The overall motor performance was investigated using Rotor-Rod. To map differences in degeneration, we compared gene expression profiles in the distal stump of degenerated nerves using Affymetrix genechips. To evaluate regeneration we monitored the recovery of motor function after crush, and then compared the fiber distribution by histology. Results: In both P 0 +/- and WT axonal degeneration triggered a change of gene expression related to axon guidance and neuroinflammation. At 7 days after lesion we found that on the lesioned side, a series of genes (Dnm3, Paxip1, Aspa, Tmod1, Frzb, Slitrk6, Thy1, Met, Sytl2, Sema3e, Fbn2, Akap6, Snord52 and Gnb4) were up-regulated less in P 0 +/- as compared to WT, whereas on the unlesioned side the expression of these genes did not differ. CMAP recovery during regeneration appeared delayed in P 0 +/-, in agreement with reduced excitability and poor performance at Rotor-Rod after one month. Conclusions: Together, these data suggest that both axonal degeneration and regeneration are impaired in the presence of mutant Schwann cells heterozygously deficient in the P 0 gene. Supported by: The Lunbeck Foundation. Disclosure: Dr. Krarup has received personal compensation for activities with Integra LifeSciences as a speaker. Dr. Krarup has received research support from Integra LifeSciences and Shire. Dr. Rosberg has nothing to disclose. Dr. Vikesa has nothing to disclose. Dr. Cilius Nielsen has nothing to disclose. Dr. Moldovan has nothing to disclose.