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Functional abnormalities in P0-deficient mice resemble human hereditary neuropathies linked to P0 gene mutations
J Zielasek1, R Martini, K V Toyka
1Department of Neurology, Julius-Maximillians-University, Würzburg, Germany.
Abstract:
Mutations in the gene encoding the transmembranous cell adhesion molecule, myelin protein zero (P0), have been reported in patients with Charcot-Marie-Tooth disease types 1B and 3 (Déjérine-Sottas disease). We have previously shown that the targeted deletion of the P0 gene in mice results in impairment of sciatic nerve conduction, and we now extend our detailed electrophysiologic investigation to the facial nerve. In concordance with histologic investigations which revealed severe hypomyelination in peripheral nerves we found the typical electrophysiologic signs of severe dysmyelination in both the facial and sciatic nerves in mice homozygously deficient for the expression of P0 (P0 -/- mice). As compared to control mice (P0+/+), nerve conduction velocities were reduced to below 10% and compound muscle action potential (CMAP) amplitudes to below 25%, while CMAP duration and excitation thresholds were markedly increased. Surprisingly, nerve conduction changes in mice heterozygously deficient for P0 (P0+/-) were only mild, were detected only in the sciatic nerve, and occurred not before 5-7 months of age. They were more prominent at age 12-13 months. Thus, P0 -/- mice resemble severe human inherited neuropathies like Charcot-Marie-Tooth disease type 3 (Déjérine-Sottas disease) with onset early in life, whereas the P0 +/- mice may resemble the milder form, CMT1B.
Insights
Mice lacking the myelin protein zero (P0) gene exhibit severe nerve damage, mimicking human inherited neuropathies. Partial P0 gene deficiency shows milder, age-dependent nerve conduction defects, similar to Charcot-Marie-Tooth disease types.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Mutations in the myelin protein zero (P0) gene are linked to Charcot-Marie-Tooth disease (CMT) types 1B and 3 (Déjérine-Sottas disease).
- Previous studies demonstrated sciatic nerve conduction impairment in P0 gene-deleted mice.
Purpose of the Study:
- To electrophysiologically investigate the impact of P0 gene deficiency on facial nerve function.
- To characterize the neuropathological phenotypes in P0-deficient mice.
Main Methods:
- Electrophysiologic assessment of sciatic and facial nerves in P0-deficient mice (P0-/- and P0+/-) and controls (P0+/+).
- Histologic examination of peripheral nerves to evaluate myelination.
- Comparison of nerve conduction velocity, compound muscle action potential (CMAP) amplitude, duration, and excitation thresholds.
Main Results:
- P0-/- mice displayed severe dysmyelination in both facial and sciatic nerves, with significantly reduced nerve conduction velocities (<10%) and CMAP amplitudes (<25%), and increased CMAP duration and excitation thresholds.
- P0+/- mice exhibited mild, age-dependent nerve conduction defects, primarily in the sciatic nerve, becoming more prominent by 12-13 months of age.
Conclusions:
- P0-/- mice serve as a model for severe inherited neuropathies like Déjérine-Sottas disease.
- P0+/- mice may represent a model for milder forms of CMT, such as CMT1B.