Developmental Regulation of Protein O-GlcNAcylation, O-GlcNAc Transferase, and O-GlcNAcase in Mammalian Brain

Abstract

O-GlcNAcylation is a common posttranslational modification of nucleocytoplasmic proteins by β-N-acetylglucosamine (GlcNAc). The dynamic addition and removal of O-GlcNAc groups to and from proteins are catalyzed by O-linked N-acetylglucosamine transferase (O-GlcNAc transferase, OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA), respectively. O-GlcNAcylation often modulates protein phosphorylation and regulates several cellular signaling and functions, especially in the brain. However, its developmental regulation is not well known. Here, we studied protein O-GlcNAcylation, OGT, and OGA in the rat brain at various ages from embryonic day 15 to the age of 2 years. We found a gradual decline of global protein O-GlcNAcylation during developmental stages and adulthood. This decline correlated positively to the total protein phosphorylation at serine residues, but not at threonine residues. The expression of OGT and OGA isoforms was regulated differently at various ages. Immunohistochemical studies revealed ubiquitous distribution of O-GlcNAcylation at all ages. Strong immunostaining of O-GlcNAc, OGT, and OGA was observed mostly in neuronal cell bodies and processes, further suggesting the role of O-GlcNAc modification of neuronal proteins in the brain. These studies provide fundamental knowledge of age-dependent protein modification by O-GlcNAc and will help guide future studies on the role of O-GlcNAcylation in the mammalian brain.

Increased O-GlcNAc levels correlate with decreased O-GlcNAcase levels in Alzheimer disease brain

“…In our study only one OGT isoform, ncOGT, could be detected and analysis of IPL and cerebellar samples revealed that ncOGT protein levels were unaffected in AD. In rat brain sOGT expression declined after maturation and no mOGT expression could be detected in adult brain [39] which may explain why no mOGT and sOGT were detected in our study. Investigation of OGT activity is necessary to allow for a meaningful discussion of the influence of OGT on O-GlcNAcylation in AD as altered or unaltered protein levels may not reflect changes in enzyme activity.…”

The Emerging Link between O-GlcNAc and Alzheimer Disease

“…OGA activity decreased after birth, whereas OGT activity increased after birth such that both reached stable levels postnatally. Immunohistochemical staining for O-GlcNAc, as well as OGA and OGT, revealed developmental changes in staining, but in postnatal mice, these markers all showed a similar distribution in the brain, with the greatest immunoreactivity being present within all classes of neurons throughout all regions of the brain (52). Other studies reported particularly high levels of OGT expression and O-GlcNAc in the cerebellar cortex and hippocampus (53,54).…”

“…In mice, one study found higher brain O-GlcNAc at 5 months compared with 3 or 13 months (51). The most rigorous study (52), in which O-GlcNAc , OGA, and OGT levels in rat brain were monitored from embryos to 2 years of age, showed that O-GlcNAc levels were most abundant in prenatal rats, and soon after birth, levels became stable. This study also showed variation in the levels of OGT splice variants and the activities of both OGT and OGA.…”

O-Linked β-N-Acetylglucosamine (O-GlcNAc) Site Thr-87 Regulates Synapsin I Localization to Synapses and Size of the Reserve Pool of Synaptic Vesicles

“…Brain O-GlcNAcylation is modulated during development and neurotransmission, suggesting potential regulatory roles of O-GlcNAc in these processes (2)(3)(4)(5)(6)(7). Current knowledge is still insufficient to draw a clear picture for the physiological function of O-GlcNAc signaling in the brain, but there is growing evidence that O-GlcNAc may regulate synaptic plasticity, a property of neurons to modulate the strength of communication between synapses that is indispensible for learning and memory (6,8).…”