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.

Links

Publisher Full Text

Authors

Saporta MA, Shy BR, Patzko A, Bai Y, Pennuto M, Ferri C, Tinelli E, Saveri P, Kirschner D, Crowther M, Southwood C, Wu X, Gow A, Feltri ML, Wrabetz L, Shy ME

Institution

Department of Neurology, Wayne State University, Detroit, MI 48201, USA.

Source

Brain : a journal of neurology 135:Pt 7 2012 Jul pg 2032-47

MeSH

Action Potentials
Animals
Axons
Cell Differentiation
Charcot-Marie-Tooth Disease
Disease Models, Animal
Early Growth Response Protein 2
Endoplasmic Reticulum
Gene Expression Regulation, Developmental
Gene Knock-In Techniques
Mice
Mice, Knockout
Mice, Transgenic
Mutation
Myelin P0 Protein
Myelin Sheath
Neural Conduction
Proto-Oncogene Proteins c-jun
Rotarod Performance Test
Schwann Cells
Sciatic Nerve
Transcription Factor CHOP
Unfolded Protein Response

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

22689911