Abstract
O-GlcNAcylation, a nutrient-sensitive post-translational modification, has emerged as a key regulator of immune and inflammatory processes. However, its role in neuroinflammation and neurodegenerative disease progression remains poorly defined. In this study, we explored how reduced O-GlcNAcylation contributes to neuroinflammatory signaling in Parkinson’s disease (PD), a disorder increasingly recognized to involve dysregulated immune–metabolic interactions. Analysis of postmortem PD substantia nigra (SN) revealed a marked reduction in global O-GlcNAcylation levels, concomitant with enhanced neuroinflammatory signatures and a predominance of pro-inflammatory microglial activation states. In a lipopolysaccharide (LPS)-induced PD mouse model, pharmacological elevation of O-GlcNAcylation through glucosamine (GlcN) or the Thiamet-G significantly ameliorated motor deficits, preserved tyrosine hydroxylase (TH)-positive dopaminergic neurons, and attenuated neuroinflammatory responses, including glial activation and inflammasome assembly. In primary microglial cultures, enhanced O-GlcNAcylation suppressed LPS-induced pro-inflammatory gene expression while promoting anti-inflammatory and homeostatic phenotypes. Mechanistically, increased O-GlcNAcylation dampened NF-κB signaling activity and reduced the production of pro-inflammatory cytokines, thereby reprogramming microglial functional states. Collectively, these findings identify O-GlcNAcylation as a critical modulator of microglial-mediated neuroinflammation and highlight its therapeutic potential for inflammation-associated neurodegenerative disorders such as PD.
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Acknowledgements
This work was supported by National Research Foundation (NRF) of Korea Grants (RS-2024-00346770). The brain research resource human brain tissues were provided by Korea Brain Bank Network (Asan Medical Center Brain Bank, Catholic Medical College Catholic Brain Bank, Inje University Brain Bank, and Severance Brain Bank) operated through the National Brain Bank Project (25-BR-09-01) and the Korean Brain cluster promotion project (RS-2021-NR057633) funded by the Ministry of Science and ICT. We would like to express our sincerest gratitude to Sun Ju Chung, Soo Jeong Nam, Joong-Seok Kim, In-Beom Kim, Sang Jin Kim, Eun Joo Chung, Byung Seok Ye, and Ji Woong Oh for providing human brain research resources.
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D.Y.K. designed and conducted the experiments, analyzed the data, prepared the figures, and wrote the main manuscript text. S.M.K. and C.L. contributed to technical assistance. I.O.H. designed the experiments, analyzed the data, and contributed to writing the main manuscript. All authors reviewed the manuscript.
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Kim, D.Y., Kim, SM., Lee, C. et al. O-GlcNAcylation regulates microglial neuroinflammation in Parkinson’s disease. npj Parkinsons Dis. (2026). https://doi.org/10.1038/s41531-026-01319-6
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DOI: https://doi.org/10.1038/s41531-026-01319-6
