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MpzR98C arrests Schwann cell development in a mouse model of early-onset Charcot-Marie-Tooth disease type 1B.
- Source :
-
Brain: A Journal of Neurology . Jul2012, Vol. 135 Issue 7, p2032-2047. 16p. - Publication Year :
- 2012
-
Abstract
- Mutations in myelin protein zero (MPZ) cause Charcot-Marie-Tooth disease type 1B. Many dominant MPZ mutations, including R98C, present as infantile onset dysmyelinating neuropathies. We have generated an R98C 'knock-in' mouse model of Charcot-Marie-Tooth type 1B, where a mutation encoding R98C was targeted to the mouse Mpz gene. Both heterozygous (R98C/+) and homozygous (R98C/R98C) mice develop weakness, abnormal nerve conduction velocities and morphologically abnormal myelin; R98C/R98C mice are more severely affected. MpzR98C is retained in the endoplasmic reticulum of Schwann cells and provokes a transitory, canonical unfolded protein response. Ablation of Chop, a mediator of the protein kinase RNA-like endoplasmic reticulum kinase unfolded protein response pathway restores compound muscle action potential amplitudes of R98C/+ mice but does not alter the reduced conduction velocities, reduced axonal diameters or clinical behaviour of these animals. R98C/R98C Schwann cells are developmentally arrested in the promyelinating stage, whereas development is delayed in R98C/+ mice. The proportion of cells expressing c-Jun, an inhibitor of myelination, is elevated in mutant nerves, whereas the proportion of cells expressing the promyelinating transcription factor Krox-20 is decreased, particularly in R98C/R98C mice. Our results provide a potential link between the accumulation of MpzR98C in the endoplasmic reticulum and a developmental delay in myelination. These mice provide a model by which we can begin to understand the early onset dysmyelination seen in patients with R98C and similar mutations. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00068950
- Volume :
- 135
- Issue :
- 7
- Database :
- Academic Search Index
- Journal :
- Brain: A Journal of Neurology
- Publication Type :
- Academic Journal
- Accession number :
- 104355496
- Full Text :
- https://doi.org/10.1093/brain/aws140