Chemical Biology Approaches to Understanding Neuronal O−GlcNAcylation

Abstract

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.