PARP1-mediated PARylation activity is essential for oligodendroglial differentiation and CNS myelination
Yan Wang,
Yanhong Zhang,
Sheng Zhang,
Bokyung Kim,
Vanessa L. Hull,
Jie Xu,
Preeti Prabhu,
Maria Gregory,
Veronica Martinez-Cerdeno,
Xinhua Zhan,
Wenbin Deng,
Fuzheng Guo
Affiliations
Yan Wang
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Yanhong Zhang
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Sheng Zhang
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Bokyung Kim
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Vanessa L. Hull
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Jie Xu
Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Preeti Prabhu
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Maria Gregory
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Veronica Martinez-Cerdeno
Department of Pathology and Laboratory Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA
Xinhua Zhan
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA
Wenbin Deng
Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, CA 95817, USA
Fuzheng Guo
Department of Neurology, School of Medicine, University of California, Davis, Davis, CA 95817, USA; Institute for Pediatric Regenerative Medicine (IPRM), Shriners Hospitals for Children, Sacramento, CA 95817, USA; Corresponding author
Summary: The function of poly(ADP-ribosyl) polymerase 1 (PARP1) in myelination and remyelination of the central nervous system (CNS) remains enigmatic. Here, we report that PARP1 is an intrinsic driver for oligodendroglial development and myelination. Genetic PARP1 depletion impairs the differentiation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes and impedes CNS myelination. Mechanistically, PARP1-mediated PARylation activity is not only necessary but also sufficient for OPC differentiation. At the molecular level, we identify the RNA-binding protein Myef2 as a PARylated target, which controls OPC differentiation through the PARylation-modulated derepression of myelin protein expression. Furthermore, PARP1’s enzymatic activity is necessary for oligodendrocyte and myelin regeneration after demyelination. Together, our findings suggest that PARP1-mediated PARylation activity may be a potential therapeutic target for promoting OPC differentiation and remyelination in neurological disorders characterized by arrested OPC differentiation and remyelination failure such as multiple sclerosis.
