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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.
Affiliation
  • Benraiss A; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA. Electronic address: abdellatif_benraiss@urmc.rochester.edu.
  • Mariani JN; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Tate A; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Madsen PM; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA; Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen 2200, Denmark.
  • Clark KM; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Welle KA; Mass Spectrometry Resource Laboratory, URMC, Rochester, NY 14642, USA.
  • Solly R; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Capellano L; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Bentley K; Department of Pathology and Laboratory Medicine, URMC, Rochester, NY 14642, USA.
  • Chandler-Militello D; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA.
  • Goldman SA; Center for Translational Neuromedicine, University of Rochester Medical Center (URMC), Rochester, NY 14642, USA; Center for Basic and Translational Neuroscience, University of Copenhagen, Copenhagen 2200, Denmark; Sana Biotechnology, Cambridge, MA, USA. Electronic address: steven_goldman@urmc.roches
Cell Rep ; 40(9): 111291, 2022 08 30.
Article in En | MEDLINE | ID: mdl-36044851
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Demyelinating Diseases / Huntington Disease / Remyelination Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2022 Document type: Article
Fulltext
Add to My VHL
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Demyelinating Diseases / Huntington Disease / Remyelination Type of study: Prognostic_studies Limits: Animals Language: En Journal: Cell Rep Year: 2022 Document type: Article