Abstract
O-GlcNAcylation is an abundant post-translational modification in the nervous system, linked to both neurodevelopmental and neurodegenerative disease. However, the mechanistic links between these phenotypes and site-specific O-GlcNAcylation remain largely unexplored. Here, we show that Ser517 O-GlcNAcylation of the microtubule-binding protein Collapsin Response Mediator Protein-2 (CRMP2) increases with age. By generating and characterizing a Crmp2S517A knock-in mouse model, we demonstrate that loss of O-GlcNAcylation leads to a small decrease in body weight and mild memory impairment, suggesting that Ser517 O-GlcNAcylation has a small but detectable impact on mouse physiology and cognitive function.
Highlights
Intracellular homeostasis and rapid cellular responses to extracellular stimuli are coordinated by combinations of different post-translational modifications on proteins
Several neuronal-specific proteins have been found to be modified by O-GlcNAc at serine and threonine residues, including Collapsin Response Mediator Protein-2 (CRMP2), an abundant protein involved in axonal guidance [59,60,61]
To investigate the sites of O-GlcNAcylation on CRMP2 in vivo, full-length CRMP2 was purified from sheep brain using ion exchange chromatography
Summary
Intracellular homeostasis and rapid cellular responses to extracellular stimuli are coordinated by combinations of different post-translational modifications on proteins. As a consequence of perturbations in cellular UDP-GlcNAc levels due to defects of metabolic homeostasis, abnormal levels of O-GlcNAcylation have been suggested to contribute to the development of chronic diseases such as diabetes, cancer and neurodegeneration [6,7]. It is well established that OGT is essential for mammalian embryogenesis, and Ogt−/− null mice are not viable [11,12,13,14]. Mice homozygous for Oga−/− mutation do not survive beyond perinatal development and show defects in glycogen mobilization [15,16]. Studies using conditional Ogt knock-out mice have revealed essential roles for O-GlcNAcylation in controlling appetite [19], browning of white adipose tissue through regulating Agouti-related protein neurons [20] and excitatory synapse maturation [21]. Missense mutations in Ogt have recently been linked to the X-linked intellectual disability syndrome OGT-XLID [22,23,24,25,26]
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