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bioRxiv · 10.1101/2020.09.27.316133

THAP1 Modulates Oligodendrocyte Maturationby Regulating ECM Degradation in Lysosomes

Yellajoshyula, D.·Pappas, S. S.·Rogers, A.·Choudhury, B.·Cookson, M.·Reed, X.·Shakkottai, V.·Giger, R.·Dauer, W. T.
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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 {beta}-glucuronidase, a GAG-catabolic lysosomal enzyme. Applying GAG-degrading enzymes or overexpressing {beta}-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.

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Yellajoshyula, D., Pappas, S. S., Rogers, A., Choudhury, B., Cookson, M., Reed, X., Shakkottai, V., Giger, R., Dauer, W. T.. 2020-09-28. THAP1 Modulates Oligodendrocyte Maturationby Regulating ECM Degradation in Lysosomes. https://doi.org/10.1101/2020.09.27.316133

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