Huntington Disease Mice Exhibit a TCF7L2-Responsive Suppression of Both Homeostatic and Compensatory Remyelination
| Autor: | Devin Chandler-Militello, Steven A. Goldman, Abdellatif Benraiss, John N. Mariani, Laetitia Capellano, Renee Solly, Karen L. de Mesy Bentley, Ashley Tate |
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| Rok vydání: | 2021 |
| Předmět: |
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 |
| Zdroj: | SSRN Electronic Journal. |
| ISSN: | 1556-5068 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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