The Essential Role of O-GlcNAcylation in Primary Sensory Neurons

Abstract

O-GlcNAcylation is the post-translational addition of β-N-acetylglucosamine to nuclear and cytoplasmic proteins. This addition is mediated by a single enzyme, O-GlcNAc transferase (OGT), which regulates a wide range of cellular processes through its thousands of protein substrates. The activity of OGT is affected by nutrient availability, and thus its role has been broadly studied in metabolic tissues. OGT is enriched in the nervous system, yet little is known about its importance in basic neuronal processes in vivo. In this work, I utilized in vivo and neuronal culture systems to determine the effects of altered O-GlcNAc dynamics in primary sensory neurons. Sensory neurons lie outside of the blood brain barrier and therefore may have a particular need for mechanisms of metabolic sensing. I show that sensory neuron-specific knockout of OGT in mice results in behavioral hyposensitivity to thermal and mechanical stimuli accompanied by decreased epidermal innervation and cell body loss in the dorsal root ganglia. These effects are observed early in postnatal development and progress as the animals age. The deficits in neuronal health are not solely due to disruption of developmental processes, because inducing OGT knockout in the sensory neurons of adult mice results in a similar decrease in nerve fiber endings and cell bodies. Significant nerve ending loss occurs prior to a decrease in cell bodies, indicative of axonal dieback that progresses to neuronal death. Cultured sensory neurons lacking OGT also exhibit decreased axonal outgrowth. These findings demonstrate that OGT is important in regulating axonal maintenance in the periphery and the overall health and survival of sensory neurons. While previous studies have focused on the essential role of OGT in mediating survival of mitotic cells, this work is the first to find that loss of OGT results in cell death in neurons. Moreover, it suggests that aberrant O-GlcNAc signaling can contribute to the development of neurodegeneration and neuropathy. Primary sensory neurons in particular are subject to degeneration in diabetes. My findings provide a foundation for understanding the role of neuronal OGT under normal physiological conditions, which will be important for understanding disease states such as diabetic neuropathy.