O-linked β-N-acetylglucosamine homeostasis in brain health and disease: From physiology to neurodevelopmental and neurodegenerative disorders

Protein O-GlcNAcylation is a dynamic and reversible post-translational modification that functions as a central nutrient-sensing mechanism linking cellular metabolism to protein function. Controlled by the opposing activities of O-linked β-N-acetylglucosamine transferase and O-GlcNAcase, O-GlcNAcylation regulates thousands of nuclear, cytoplasmic, synaptic, and mitochondrial proteins involved in gene expression, neuronal differentiation, synaptic plasticity, proteostasis, mitochondrial homeostasis, and neuroimmune signaling. The brain exhibits particularly high O-linked β-N-acetylglucosamine activity, reflecting its exceptional metabolic demands and the need to rapidly couple nutrient availability with neuronal function. Emerging evidence demonstrates that precise regulation of O-linked β-N-acetylglucosamine cycling is indispensable throughout the lifespan, from embryonic neurodevelopment to healthy brain aging. Conversely, disruption of O-linked β-N-acetylglucosamine homeostasis caused by genetic defects, metabolic disturbances, or environmental stress contributes to neurodevelopmental disorders. In the aging brain, impaired glucose metabolism and insulin resistance reduce O-GlcNAcylation, promoting mitochondrial dysfunction, neuroinflammation, proteostasis failure, and the accumulation of pathogenic proteins. Consequently, dysregulated O-linked β-N-acetylglucosamine signaling has emerged as a convergent mechanism underlying brain disorders spanning neurodevelopment to neurodegeneration. Although clinical translation remains challenging, growing evidence supports O-GlcNAcylation as a master regulator of brain homeostasis and a promising therapeutic target for neurological disorders. Collectively, this review highlights O-linked β-N-acetylglucosamine signaling as a molecular bridge connecting early brain development, adulthood, and aging, providing an integrated framework for understanding brain physiology and disease.