THAP1 Modulates Oligodendrocyte Maturation by Regulating ECM Degradation in Lysosomes

Abstract

Mechanisms controlling myelination during 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 ECM composition by regulating glycosaminoglycan (GAG) catabolism within oligodendrocyte progenitor cells (OPCs). Thap1-/- OPCs accumulate and secrete excess GAGs, inhibiting their maturation through an auto-inhibitory mechanism. THAP1 controls GAG metabolism by binding to and regulating the GusB gene encoding β-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading 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.

A pathogenic DYT-THAP1 dystonia mutation causes hypomyelination and loss of YY1 binding

“…To further assess the effect of the F81L mutation, we sought to identify genes that are highly transcriptionally sensitive to THAP1. We examined 4 datasets that include genes significantly altered by THAP1 loss in brain tissue (separate datasets for cortex, striatum, and cerebellum), and in primary cultures of oligodendrocyte progenitor cells (16), as well as ChIP-seq data from ENCODE (Figure 1C and Table S1). We identified 5 genes (Ech1, Cuedc2, Dpagt1, Prepl and Cln3) that were common to all of these datasets (Figure 1C).…”