THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes

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

doi:10.1073/pnas.2100862118

THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes

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

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5 Scopus citations

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 language	English (US)
Article number	e2100862118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	31
DOIs	https://doi.org/10.1073/pnas.2100862118
State	Published - Aug 3 2021

Keywords

CNS myelination
Extracellular matrix
Neurodevelopmental disease

ASJC Scopus subject areas

General

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10.1073/pnas.2100862118

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Yellajoshyula, D., Pappas, S. S., Rogers, A. E., Choudhury, B., Reed, X., Ding, J., Cookson, M. R., Shakkottai, V. G., Giger, R. J., & Dauer, W. T. (2021). THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes. Proceedings of the National Academy of Sciences of the United States of America, 118(31), Article e2100862118. https://doi.org/10.1073/pnas.2100862118

Yellajoshyula, D, Pappas, SS, Rogers, AE, Choudhury, B, Reed, X, Ding, J, Cookson, MR, Shakkottai, VG, Giger, RJ & Dauer, WT 2021, 'THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 31, e2100862118. https://doi.org/10.1073/pnas.2100862118

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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.",

keywords = "CNS myelination, Extracellular matrix, Neurodevelopmental disease",

author = "Dhananjay Yellajoshyula and Pappas, {Samuel S.} and Rogers, {Abigail E.} and Biswa Choudhury and Xylena Reed and Jinhui Ding and Cookson, {Mark R.} and Shakkottai, {Vikram G.} and Giger, {Roman J.} and Dauer, {William T.}",

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AU - Reed, Xylena

AU - Ding, Jinhui

AU - Cookson, Mark R.

AU - Shakkottai, Vikram G.

AU - Giger, Roman J.

AU - Dauer, William T.

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N2 - 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.

AB - 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.

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KW - Extracellular matrix

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THAP1 modulates oligodendrocyte maturation by regulating ECM degradation in lysosomes

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