4.8 Article

A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice

Journal

CELL REPORTS
Volume 40, Issue 9, Pages -

Publisher

CELL PRESS
DOI: 10.1016/j.celrep.2022.111291

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Funding

  1. Hereditary Disease Foundation
  2. NIH [R01NS110776]
  3. Lundbeck Foundation
  4. Sana Biotechnology

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Huntington's disease (HD) is characterized by defective oligodendroglial differentiation and white matter disease. This study reveals a link between oligodendrocyte progenitor cell (OPC) dysfunction and impaired myelin maintenance in adult HD patients. The downregulation of genes associated with oligodendrocyte differentiation and myelinogenesis is identified as a major driver of this dysfunction, and Tcf7l2 signaling is found to be a potential therapeutic target.
Huntington's disease (HD) is characterized by defective oligodendroglial differentiation and white matter dis-ease. Here, we investigate the role of oligodendrocyte progenitor cell (OPC) dysfunction in adult myelin main-tenance in HD. We first note a progressive, age-related loss of myelin in both R6/2 and zQ175 HD mice compared with wild-type controls. Adult R6/2 mice then manifest a significant delay in remyelination following cuprizone demyelination. RNA-sequencing and proteomic analysis of callosal white matter and OPCs isolated from both R6/2 and zQ175 mice reveals a systematic downregulation of genes associated with oligodendrocyte differentiation and myelinogenesis. Gene co-expression and network analysis predicts repressed Tcf7l2 signaling as a major driver of this expression pattern. In vivo Tcf7l2 overexpression restores both myelin gene expression and 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.

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