Essential role of O-GlcNAc transferase (OGT) in the physiological functions of dopaminergic neuron

Abstract

O-GlcNAcylation is one of the pivotal post-translational modifications modulating many fundamental cellular processes, including transcription, translation, and signal transduction. It attaches O-linked N-acetylglucosamine (O-GlcNAc) moieties to serine, threonine residues of cytoplasmic, nuclear, and mitochondrial proteins. Interestingly, O-GlcNAc modification and two enzymes governing O-GlcNAcylation are highly abundant in the mammalian brain. Previous studies have revealed the role of O-GlcNAcylation in modulating neuronal and synaptic functions. In addition, the pathological relevance of O-GlcNAc modification in neurological diseases has recently begun to emerge. Recently, we discovered that elevation of O-GlcNAcylation can alleviate neurodegeneration in an animal model of PD. Despite these findings, our understanding of the exact functional role of O-GlcNAcylation in the dopamine system remains rudimentary. Here, we show that dopaminergic neuron-specific knockout of OGT at the young age led to the alterations in inhibitory synaptic transmission, input resistance, action potential firing, and attenuated Ih current in the dopaminergic neurons, potentially indicating early physiological adaptations before neurodegeneration. Furthermore, not only chronic, but also acute deletion of OGT at the adult stage caused dopaminergic neurons death, eventually resulting in the degeneration of dopamine system. These results demonstrate that OGT and O-GlcNAcylation may play an essential role in regulating the structures and functions of dopaminergic neurons.