Dysmyelination not demyelination causes neurological symptoms in preweaned mice in a murine model of Cockayne syndrome

摘要

Cockayne syndrome (CS) is a rare autosomal recessive neurode generative disease that is associated with mutations in either of two transcription-coupled DNA repair genes, CSA or CSB. Mice with a targeted mutation in the Csb gene (Cs-b~(m/m)) exhibit a milder phe notype compared with human patients with mutations in the orthologous CSB gene. Mice mutated in Csb were crossed with mice lacking Xpc (Xp-c~(-/-)), the global genome repair gene, to enhance the pathological symptoms. These Cs-b~(m/m).Xp-c~(-/-) mice were nor mal at birth but exhibited progressive failure to thrive, whole-body wasting, and ataxia and died at approximately postnatal day 21. Characterization of Cs-b~(m/m).Xp-c~(-/-) brains at postnatal stages dem onstrated widespread reduction of myelin basic protein (MBP) and myelin in the sensorimotor cortex, the stratum radiatum, the cor pus callosum, and the anterior commissure. Quantification of in dividual axons by electron microscopy showed a reduction in both the number of myelinated axons and the average diameter of myelin surrounding the axons. There were no significant differ ences in proliferation or oligodendrocyte differentiation between Cs-b~(m//m).Xp-c-/- and Cs-b~(m/+).Xp-c~(-/-) mice. Rather, Cs-b(m/m).Xp-c(-/-) oligodendrocytes were unable to generate sufficient MBP or to maintain the proper myelination during early development. Csb is a multifunctional protein regulating both repair and the tran scriptional response to reactive oxygen through its interaction with histone acetylase p300 and the hypoxia-inducible factor (HIF)1 pathway. On the basis of our results, combined with that of others, we suggest that in Csb the transcriptional response predominates during early development, whereas a neurodegenerative response associated with repair deficits predominates in later life.