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bioRxiv · 10.64898/2026.03.02.709210

Global O-GlcNAcome Identifies O-GlcNAcylated Proteins Regulating Oligodendrocyte Precursor Cells Differentiation

Jiang, X.·Zhang, C.·Li, P.·Ye, K.·Song, Y.·Zhang, M.
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Abstract

Oligodendrocyte precursor cells (OPCs) differentiate into myelinating oligodendrocytes to form the myelin sheaths essential for neural function, a process frequently compromised during aging and in diseases like multiple sclerosis. However, the regulatory landscape of myelination remains incompletely understood. Here, we perform a comprehensive proteomic analysis of the O-GlcNAcome in postnatal day 0 mouse OPCs, identifying 165 O-GlcNAcylation sites across 118 proteins. These proteins are mostly nuclear and characterized by single-site modifications. Comparative analysis identifies 74 novel sites and 22 proteins uniquely O-GlcNAcylated in OPCs. Molecular docking suggestes that O-GlcNAcylation might act as a dynamic regulator of OPC differentiation. Notably, global O-GlcNAcylation levels increase during the OPC-to-oligodendrocyte transition. By integrating our findings with multiple sclerosis-related transcriptomic and proteomic datasets, we identify candidate proteins linking O-GlcNAc dysregulation to demyelination. Among these, Vimentin (Vim) exhibits a pronounced age-dependent discrepancy between decreased protein levels and elevated mRNA expression during differentiation. We validate Threonine 35 and 63 as key O-GlcNAcylation sites on Vimentin. Functional assays confirm that blocking Vimentin O-GlcNAcylation enhance the OPC differentiation. Collectively, our study establishes the first O-GlcNAc landscape for OPCs and suggests O-GlcNAcylation as a pivotal regulator for OPC differentiation.

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Jiang, X., Zhang, C., Li, P., Ye, K., Song, Y., Zhang, M.. 2026-03-04. Global O-GlcNAcome Identifies O-GlcNAcylated Proteins Regulating Oligodendrocyte Precursor Cells Differentiation. https://doi.org/10.64898/2026.03.02.709210

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