A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice
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A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice. / Benraiss, Abdellatif; Mariani, John N.; Tate, Ashley; Madsen, Pernille M.; Clark, Kathleen M.; Welle, Kevin A.; Solly, Renee; Capellano, Laetitia; Bentley, Karen; Chandler-Militello, Devin; Goldman, Steven A.
In: Cell Reports, Vol. 40, No. 9, 111291, 2022.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A TCF7L2-responsive suppression of both homeostatic and compensatory remyelination in Huntington disease mice
AU - Benraiss, Abdellatif
AU - Mariani, John N.
AU - Tate, Ashley
AU - Madsen, Pernille M.
AU - Clark, Kathleen M.
AU - Welle, Kevin A.
AU - Solly, Renee
AU - Capellano, Laetitia
AU - Bentley, Karen
AU - Chandler-Militello, Devin
AU - Goldman, Steven A.
N1 - Publisher Copyright: © 2022 The Authors
PY - 2022
Y1 - 2022
N2 - Huntington's disease (HD) is characterized by defective oligodendroglial differentiation and white matter disease. Here, we investigate the role of oligodendrocyte progenitor cell (OPC) dysfunction in adult myelin maintenance 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.
AB - Huntington's disease (HD) is characterized by defective oligodendroglial differentiation and white matter disease. Here, we investigate the role of oligodendrocyte progenitor cell (OPC) dysfunction in adult myelin maintenance 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.
KW - CP: Neuroscience
KW - glia
KW - glial progenitor cell
KW - gliogenesis
KW - Huntington's disease
KW - myelin
KW - myelination
KW - neurodegenerative disease
KW - oligodendrocyte progenitor cell
KW - Tcf7l2
U2 - 10.1016/j.celrep.2022.111291
DO - 10.1016/j.celrep.2022.111291
M3 - Journal article
C2 - 36044851
AN - SCOPUS:85137061203
VL - 40
JO - Cell Reports
JF - Cell Reports
SN - 2211-1247
IS - 9
M1 - 111291
ER -
ID: 343130807