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

被引：16

作者：

Benraiss, Abdellatif ^{[1
]}

Mariani, John N. ^{[1
]}

Tate, Ashley ^{[1
]}

Madsen, Pernille M. ^{[1
,2
]}

Clark, Kathleen M. ^{[1
]}

Welle, Kevin A. ^{[3
]}

Solly, Renee ^{[1
]}

Capellano, Laetitia ^{[1
]}

Bentley, Karen ^{[4
]}

Chandler-Militello, Devin ^{[1
]}

Goldman, Steven A. ^{[1
,2
,5
]}

机构：

[1] Univ Rochester Med Ctr URMC, Ctr Translat Neuromed, Rochester, NY 14642 USA

[2] Univ Copenhagen, Ctr Basic & Translat Neurosci, DK-2200 Copenhagen, Denmark

[3] URMC, Mass Spectrometry Resource Lab, Rochester, NY 14642 USA

[4] URMC, Dept Pathol, Lab Med, Rochester, NY 14642 USA

[5] Sana Biotechnol, Cambridge, MA 02139 USA

来源：

CELL REPORTS | 2022年 / 40卷 / 09期

关键词：

WHITE-MATTER; OLIGODENDROCYTE DIFFERENTIATION; NEURAL PROGENITORS; GENE-EXPRESSION; DEMYELINATION; TCF7L2; ENVIRONMENT; MODELS;

D O I：

10.1016/j.celrep.2022.111291

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：22

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