O-GlcNAcylation regulates microglial neuroinflammation in Parkinson's disease.

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.