UCSF

The post-translational modification, O-linked N-Acetylglucosamine (O-GlcNAc) is a major regulator of aging, neurodegenerative disease, and stem cell function. Addition and removal of O-GlcNAc is tightly controlled by O-GlcNAc transferase (Ogt) and O-GlcNAcase (OGA), respectively. Reducing the expression of either of these enzymes has previously been shown to alter neurogenesis in the developing brain. Moreover, our lab has previously identified an age-related decrease in hippocampal O-GlcNAc levels underlying age-related impairments in cognitive function. Notwithstanding, whether O-GlcNAc plays a role in adult hippocampal neurogenesis has yet to be explored. Here we investigate the role of O-GlcNAc in regulating the decline of adult hippocampal neurogenesis. First, we identify an age-related loss of neural stem cell (NSC) O-GlcNAcylation concurrent with an increase in gliogenesis. Mechanistically, we demonstrate that loss of STAT3 O-GlcNAcylation in NSCs promotes gliogenesis at the expense of neurogenesis and NSC self-renewal. Next, we examine the role of the mitochondrial isoform of Ogt (mOGT). We identify an age-related increase in mOGT levels capable of driving NSC depletion by promoting aberrant neuronal differentiation. Finally, we explore the role of OGA in regulating age-related regenerative decline in the brain. While impairing OGA does not appear to alter neuronal differentiation, we identify a change in non-neuronal differentiation in vivo. Taken together, these data implicate O-GlcNAc as a major regulator of adult hippocampal neurogenesis and posit O-GlcNAc as a therapeutic target for combatting age-related regenerative decline in the brain.