Upregulation of large myelin protein zero leads to Charcot–Marie–Tooth disease-like neuropathy in mice
| Autor: | Jingjing Cui, Nobuhiko Ohno, Yoshihide Yamaguchi, Yoshinori Otani, Hiroko Baba |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Gene isoform Translation Heterozygote Transgene Myelin biology and repair Medicine (miscellaneous) Mice Transgenic Biology Gene mutation Motor Activity medicine.disease_cause Molecular neuroscience General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Myelin Mice 0302 clinical medicine Downregulation and upregulation Charcot-Marie-Tooth Disease medicine Animals Protein Isoforms lcsh:QH301-705.5 Myelin Sheath Gene Editing Mutation Myelin protein zero Translational readthrough Homozygote fungi Endoplasmic Reticulum Stress Axons Cell biology Up-Regulation Demyelinating diseases Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Phenotype nervous system lcsh:Biology (General) Peripheral nervous system General Agricultural and Biological Sciences Myelin P0 Protein 030217 neurology & neurosurgery |
| Zdroj: | Communications Biology, Vol 3, Iss 1, Pp 1-15 (2020) Communications Biology |
| ISSN: | 2399-3642 |
| Popis: | 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. Otani et al. show that upregulation of large myelin protein zero (L-MPZ), an isoform of myelin protein zero (P0) which contains an extended polypeptide synthesized by translational readthrough, can cause neuropathy, using mice that produce L-MPZ instead of P0. This study suggests the importance of keeping L-MPZ low for the proper functioning of myelin. |
| Databáze: | OpenAIRE |
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