Intracellular and extracellular O-linked N-acetylglucosamine in the nervous system

Addition of O-linked N-acetylglucosamine (O-GlcNAc) to the hydroxyl group of serine and threonine residues (O-GlcNAcylation) is a post-translational modification common to multicellular eukaryotes. To date, O-GlcNAcylations have been divided into two categories: the first involves nucleocytoplasmic and mitochondrial (intracellular) O-GlcNAcylation catalyzed by O-GlcNAc transferase (OGT), and the second involves O-GlcNAcylation in the secretory pathways (extracellular) catalyzed by epidermal growth factor (EGF) domain-specific O-GlcNAc transferase (EOGT). Intracellular O-GlcNAcylation is involved in essential cellular and physiological processes such as synaptic activity, neuronal morphogenesis, and learning and memory. Moreover, intracellular O-GlcNAc might have a neuroprotective effect, protecting against neurodegenerative diseases such as Alzheimer's disease. EGF repeats on extracellular matrix proteins and the extracellular region of transmembrane proteins have recently been found to be modified by O-GlcNAc in the mouse cerebral cortex. EOGT is responsible for Adams-Oliver syndrome, a rare congenital disorder characterized by aplasia cutis congenita and terminal transverse limb defects, often accompanied by cardiovascular and neurological defects. Thus, a mechanistic understanding of O-GlcNAc in the regulation of its target proteins is of importance from both a basic science and a clinical-translational perspective. In this review, we summarize the current understanding of the physiological and pathological significances of both types of O-GlcNAcylations found in the nervous system.