Brain O-GlcNAcylation in Neurodegenerative Diseases: Context-Dependent Mechanisms and Precision Therapeutic...

O-linked β-N-acetylglucosamine modification (O-GlcNAcylation) is a dynamic, nutrient-sensitive post-translational modification that couples hexosamine biosynthesis pathway flux to protein function in neurons and glia. This reversible cycling, catalyzed by O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), integrates glucose, glutamine, acetyl-CoA, and nucleotide metabolism with synaptic activity, mitochondrial adaptation, transcriptional regulation, proteostasis, and neuroimmune signaling. Dysregulated O-GlcNAc cycling has been implicated in major neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Huntington's disease (HD), through effects on disease-related proteins, autophagy, mitochondrial function, and inflammatory networks. However, available evidence does not support a universal model in which global O-GlcNAc elevation is uniformly protective or global reduction is uniformly pathogenic. In this mechanistic narrative review, we integrate disease-specific and substrate-focused findings while distinguishing relatively mature translational evidence from model-based or hypothesis-generating observations. We propose a state-resolved framework in which disease-relevant O-GlcNAc states are interpreted across biological contexts, substrate/site specificity, and intervention dynamics. This framework helps reconcile divergent findings across experimental systems and highlights the limitations of indiscriminate global pathway modulation. Although OGA inhibitors represent the most advanced therapeutic strategy, their broad substrate effects underscore the need for pharmacodynamic biomarkers, human validation, brain-targeted delivery, and state-resolved approaches. Moving from bulk O-GlcNAc measurements toward precise correction of disease-relevant O-GlcNAc states across defined biological contexts will be essential for translating this biology into clinically meaningful interventions.