| Autor: |
Otani Y; Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan., Ohno N; Department of Anatomy, Division of Histology and Cell Biology, School of Medicine, Jichi Medical University, Shimotsuke, Japan.; Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki, Japan., Cui J; Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan., Yamaguchi Y; Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan. yoshiy@toyaku.ac.jp., Baba H; Department of Molecular Neurobiology, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan. |
| Abstrakt: |
Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy mainly caused by gene mutation of peripheral myelin proteins including myelin protein zero (P0, MPZ). Large myelin protein zero (L-MPZ) is an isoform of P0 that contains an extended polypeptide synthesized by translational readthrough at the C-terminus in tetrapods, including humans. The physiological role of L-MPZ and consequences of an altered L-MPZ/P0 ratio in peripheral myelin are not known. To clarify this, we used genome editing to generate a mouse line (L-MPZ mice) that produced L-MPZ instead of P0. Motor tests and electrophysiological, immunohistological, and electron microscopy analyses show that homozygous L-MPZ mice exhibit CMT-like phenotypes including thin and/or loose myelin, increased small-caliber axons, and disorganized axo-glial interactions. Heterozygous mice show a milder phenotype. These results highlight the importance of an appropriate L-MPZ/P0 ratio and show that aberrant readthrough of a myelin protein causes neuropathy. |
