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Huntington Disease Mice Exhibit a TCF7L2-Responsive Suppression of Both Homeostatic and Compensatory Remyelination
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2021
- Publisher :
- Elsevier BV, 2021.
-
Abstract
- Huntington’s disease (HD) is characterized by defective oligodendroglial differentiation and white matter disease. Here, we investigated the role of glial progenitor cell (GPC) dysfunction in adult myelin maintenance in HD. We first noted a progressive, age-related loss of myelin in both R6/2 and zQ175 HD mice, compared to wild-type controls. As adults, R6/2 mice then manifested a significant delay in remyelination following cuprizone demyelination. RNA-Sequencing of GPCs from both R6/2 and zQ175 mice revealed a systematic down-regulation of genes associated with oligodendrocyte differentiation and myelinogenesis relative to controls. Gene co-expression and network analysis predicted repressed TCF7L2 signaling as a major driver of this expression pattern. In vivo TCF7L2 overexpression proved sufficient to restore both myelin gene expression and normal remyelination in demyelinated R6/2 mice. These data causally link impaired TCF7L2-dependent transcription to the poor development and homeostatic retention of myelin in HD, and provide a mechanism for its therapeutic restoration.
- Subjects :
- History
Polymers and Plastics
Oligodendrocyte differentiation
Biology
medicine.disease
Industrial and Manufacturing Engineering
Cell biology
White matter
Myelin
medicine.anatomical_structure
Huntington's disease
Myelin maintenance
medicine
Myelinogenesis
Business and International Management
Remyelination
Gliogenesis
Subjects
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi...........e409fcbcfe1390b43912b29a53f80ddd