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

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  • Abdellatif Benraiss
  • John N. Mariani
  • Ashley Tate
  • Pernille M. Madsen
  • Kathleen M. Clark
  • Kevin A. Welle
  • Renee Solly
  • Laetitia Capellano
  • Karen Bentley
  • Devin Chandler-Militello
  • Goldman, Steven Alan
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.
OriginalsprogEngelsk
Artikelnummer111291
TidsskriftCell Reports
Vol/bind40
Udgave nummer9
Antal sider22
ISSN2211-1247
DOI
StatusUdgivet - 2022

Bibliografisk note

Funding Information:
Supported by the Hereditary Disease Foundation , NIH R01NS110776 , the Lundbeck Foundation , and Sana Biotechnology . We are grateful to both the URMC Genomics Research Center and the URMC Shared Resource Laboratory, for assistance with electron microscopy and mass spectrometry, respectively.

Funding Information:
Supported by the Hereditary Disease Foundation, NIH R01NS110776, the Lundbeck Foundation, and Sana Biotechnology. We are grateful to both the URMC Genomics Research Center and the URMC Shared Resource Laboratory, for assistance with electron microscopy and mass spectrometry, respectively. D.C.-M. prepared the OPCs used in the study; A.T. and R.S. performed the histological processing, imaging, and quantitative analyses; P.M.M. and A.B. generated the viral expression vectors used; K.M.C. performed the western blots of HD and WT white matter; L.C. performed the in vivo overexpression study and qPCRs; K.A.W. and J.N.M. were responsible for the mass spectrometry; K.B. was responsible for the electron microscopic imaging; J.N.M. performed the genomic analyses; A.B. and S.A.G. designed the study, analyzed data, and wrote the manuscript. S.A.G. is a part-time employee and stockholder of Sana Biotechnology, a cell therapy company, and his lab receives sponsored research support from Sana. S.A.G. is also a co-founder and adviser to CNS2 Therapeutics, another cell therapy company. None of the work described in this paper overlaps with his work with those companies. D.C.-M. is also a consultant to Sana.

Publisher Copyright:
© 2022 The Authors

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