Investigating the role of O-GlcNAcylation in regulating synaptic and cognitive decline with age
Cognitive decline is emblematic of brain aging, ascribed in large part to age-related changes occurring at neuronal synapses. Dynamic post-translational protein modifications – in particular phosphorylation and O-GlcNAcylation – are known regulators of synaptic and cognitive function. However, how the landscape of synaptic PTMs changes with age has yet to be elucidated. In this study, age-dependent changes in phosphorylation and O-GlcNAcylation were characterized using a proteomics-based approach. Analyses implicate age-dependent changes in dynamic PTMs in age-related cognitive decline and vulnerability to neurodegenerative disorders, including Parkinson’s and Alzheimer’s disease. The functional relevance of age-related changes in PTMs, in particular of O-GlcNAcylation, was also investigated in vivo. Mimicking age-related decreased levels of neuronal O-GlcNAc recapitulated features of molecular, synaptic, and cognitive aging in mice, implicating that changes in O-GlcNAc promote brain dysfunction during aging. Moreover, increasing O-GlcNAcylation in the adult hippocampus enhanced cognition, proposing O-GlcNAc as a target for brain rejuvenation. Ultimately, this study proposes dynamic PTMs as novel molecular drivers of brain aging, and provides the foundation for future mechanistic studies to investigate site-specific molecular changes underlying synaptic and cognitive decline with age.