| First Author | Avila RL | Year | 2010 |
| Journal | J Biol Chem | Volume | 285 |
| Issue | 53 | Pages | 42001-12 |
| PubMed ID | 20937820 | Mgi Jnum | J:167380 |
| Mgi Id | MGI:4868150 | Doi | 10.1074/jbc.M110.166967 |
| Citation | Avila RL, et al. (2010) P0 (protein zero) mutation S34C underlies instability of internodal myelin in S63C mice. J Biol Chem 285(53):42001-12 |
| abstractText | P0 constitutes 50-60% of protein in peripheral nerve myelin and is essential for its structure and stability. Mutations within the P0 gene (MPZ) underlie a variety of hereditary neuropathies. MpzS63C transgenic mice encode a P0 with a serine to cysteine substitution at position 34 in the extracellular domain of mature P0 (P0S34C), associated with the hypomyelinating Dejerine-Sottas syndrome in human. S63C mice develop a dysmyelinating neuropathy, with packing defects in peripheral myelin. Here, we used x-ray diffraction to examine time-dependent packing defects in unfixed myelin. At approximately 7 h post-dissection, WT and S63C(+/+) myelin showed native periods (175 A) with the latter developing at most a few percent swollen myelin, whereas up to approximately 50% of S63C(+/-) (mutant P0 on heterozygous P0 null background) or P0(+/-) myelin swelled to periods of approximately 205 A. In the same time frame, S63C(-/-) myelin was stable, remaining swollen at approximately 210 A. Surprisingly, treatment of whole S63C(-/-) nerves with a reducing agent completely reverted swollen arrays to native spacing and also normalized the swollen arrays that had formed in S63C(+/-) myelin, the genotype most closely related to the human disorder. Western blot revealed P0-positive bands at approximately 27 and approximately 50 kDa, and MALDI-TOF mass spectrometry showed these bands consisted of Ser(34)-containing peptides or P0 dimers having oxidized Cys(34) residues. We propose that P0S34C forms ectopic disulfide bonds in trans between apposed Cys(34) side chains that retard wrapping during myelin formation causing hypomyelination. Moreover, the new bonds create a packing defect by stabilizing swollen membrane arrays that leads to demyelination. |
