The potential role of the posttranslational modification of proteins with O-linked N-acetyl-β-d-glucosamine (O-GlcNAc) in the pathogenesis of Alzheimer disease (AD) has been studied extensively, yet the exact function of O-GlcNAc in AD remains elusive. O-GlcNAc cycling is facilitated by only two highly conserved enzymes: O-GlcNAc transferase (OGT) catalyzes the addition, while O-GlcNAcase (OGA) catalyzes the removal of GlcNAc from proteins. Studies analyzing global O-GlcNAc levels in AD brain have produced inconsistent results and the reasons for altered O-GlcNAcylation in AD are still poorly understood. In this study, we show a 1.2-fold increase in cytosolic protein O-GlcNAc modification in AD brain when compared to age-matched controls. Interestingly, O-GlcNAc changes seem to be attributable to differential modification of a few individual proteins. While our finding of augmented O-GlcNAcylation concurs with some reports, it is contrary to others demonstrating decreased O-GlcNAc levels in AD brain. These conflicting results emphasize the need for further studies providing conclusive evidence on the subject of O-GlcNAcylation in AD. We further demonstrate that, while OGT protein levels are unaffected in AD, OGA protein levels are significantly decreased to 75% of those in control samples. In addition, augmented protein O-GlcNAc modification correlates to decreased OGA protein levels in AD subjects. While OGA inhibitors are already being tested for AD treatment, our results provide a strong indication that the general subject of O-GlcNAcylation and specifically its regulation by OGA and OGT in AD need further investigation to conclusively elucidate its potential role in AD pathogenesis and treatment.
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http://dx.doi.org/10.1016/j.bbadis.2014.05.014 | DOI Listing |
J Cell Physiol
January 2025
Department of Oral Morphology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan.
Our previous study revealed a link between O-GlcNAc transferase (OGT) localization and protein phosphatase 2A (PP2A) activity in osteoblast. Given the association of PP2A downregulation with osteoblast differentiation, we hypothesized that OGT localization changes during this process. We examined OGT localization in MC3T3-E1 cells undergoing differentiation under normal and high glucose conditions.
View Article and Find Full Text PDFFront Immunol
January 2025
Institute for Immunodeficiency, Center for Chronic Immunodeficiency, University Medical Center Freiburg, Freiburg, Germany.
Background: Hypomorphic mutations in the () gene cause a glycosylation disorder that leads to immunodeficiency. It is often associated with recurrent infections and atopy. The exact etiology of this condition remains unclear.
View Article and Find Full Text PDFPrev Nutr Food Sci
December 2024
Aging and Metabolism Research Group, Food Functionality Research, Korea Food Research Institute, Wanju 55365, Korea.
Vascular smooth muscle cells (VSMCs) undergo metabolic pathway transitions, including aerobic glycolysis, fatty acid oxidation, and amino acid metabolism, which are important for their function. Metabolic dysfunction in VSMCs can lead to age-related vascular diseases. -GlcNAcylation, a nutrient-dependent posttranslational modification linked specifically to glucose metabolism, plays an important role in this context.
View Article and Find Full Text PDFSci Rep
January 2025
Department of Anatomy and Cell Biology, College of Medicine, Chung-Ang University, Seoul, 06974, South Korea.
Patients with estrogen receptor-positive breast cancer undergoing continuous adjuvant hormone therapy often experience delayed recurrence with tamoxifen use, potentially causing adverse effects. However, the lack of biomarkers hampers patient selection for extended endocrine therapy. This study aimed to elucidate the molecular mechanisms underlying delayed recurrence and identify biomarkers.
View Article and Find Full Text PDFCell Biochem Biophys
January 2025
Department of Obstetrics, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, 361003, China.
O-linked N-acetylglucosamine transferase (OGT)-catalyzed O-linked N-acetylglucosamine glycosylation (O-GlcNAcylation) is closely associated with diabetes progression. This study aims to investigate the mechanism of OGT in regulating endothelial dysfunction in gestational diabetes mellitus (GDM). Expressions of OGT, O-linked N-acetylglucosamine (O-GlcNAc), enhancer of zeste homolog 2 (EZH2), and HEK27me3 in human umbilical vein endothelial cells (HUVECs) and GDM-derived HUVECs (GDM-HUVECs) were assessed by western blot.
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