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

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.

Automated summary

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.