THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes

Dhananjay Yellajoshyula, Samuel Pappas, Abigail E. Rogers, Biswa Choudhury, Xylena Reed, Jinhui Ding, Mark R. Cookson, Vikram G. Shakkottai, Roman J. Giger, William Dauer

Research output: Contribution to journalArticlepeer-review

Abstract

Mechanisms controlling myelination during central nervous system (CNS) maturation play a pivotal role in the development and refinement of CNS circuits. The transcription factor THAP1 is essential for timing the inception of myelination during CNS maturation through a cell-autonomous role in the oligodendrocyte lineage. Here, we demonstrate that THAP1 modulates the extracellular matrix (ECM) composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1-/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an autoinhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAGdegrading enzymes or overexpressing β-glucuronidase rescues Thap1-/- OL maturation deficits in vitro and in vivo. Our studies establish lysosomal GAG catabolism within OPCs as a critical mechanism regulating oligodendrocyte development.

Original languageEnglish (US)
Article numbere2100862118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number31
DOIs
StatePublished - Aug 3 2021

Keywords

  • CNS myelination
  • Extracellular matrix
  • Neurodevelopmental disease

ASJC Scopus subject areas

  • General

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