Chemical Biology Approaches to Understanding Neuronal O–GlcNAcylation

O-linked β-N-acetylglucosamine (O–GlcNAc) is a ubiquitous post-translational modification in mammals, decorating thousands of intracellular proteins. O–GlcNAc cycling is an essential regulator of myriad aspects of cell physiology and is dysregulated in numerous human diseases. Notably, O–GlcNAcylation is abundant in the brain and numerous studies have linked aberrant O–GlcNAc signaling to various neurological conditions. However, the complexity of the nervous system and the dynamic nature of protein O–GlcNAcylation have presented challenges for studying of neuronal O–GlcNAcylation. In this context, chemical approaches have been a particularly valuable complement to conventional cellular, biochemical, and genetic methods to understand O–GlcNAc signaling and to develop future therapeutics. Here we review selected recent examples of how chemical tools have empowered efforts to understand and rationally manipulate O–GlcNAcylation in mammalian neurobiology.