Abstract
O-GlcNAcylation is a highly dynamic post-translational modification that plays a key role in regulating phosphorylation of protein and cell survival. The proteins O-GlcNAcylation level is regulated dynamically by O-GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA). Although previous studies have suggested the role of O-GlcNAcylation in neurodegenerative diseases, the mechanism of O-GlcNAcylation in Alzheimer's disease (AD) remains unclear. The decrease of O-GlcNAcylation by alloxan, an OGT inhibitor, and increase by NAG-thiazolines (NAG-Ae), an O-GlcNAcase inhibitor were tested to investigate the effects of O-GlcNAc alteration on AD like neurodegeneration in SK-N-SH cells. The level of O-GlcNAcylation was decreased in alloxan treated cells and increased in NAG-Ae treated cells. Meanwhile, it was observed that both abnormal phosphorylation of NFs in cell bodies and apoptosis induced by alloxan treatment can be resisted by pretreatment or simultaneous treatment with appropriate NAG-Ae. These results demonstrated that increasing O-GlcNAc with NAG-Ae protected AD like neurodegeneration from NFs hyperphosphorylation and the cell loss, suggesting the role of O-GlcNAc in the pathogenesis and therapy of AD.
Highlights
Alzheimer’s disease (AD) is a common neurodegenerative disease
We detected the level of O-GlcNAcylation with antibody RL2 to recognize the O-Glycosylation of protein in cells treated with alloxan and NAG-Ae
The level of O-GlcNAcylation was decreased in a dose-dependent manner as the cells exposed to alloxan (Fig. 1A, B)
Summary
Alzheimer’s disease (AD) is a common neurodegenerative disease. In AD brain, the aggregation of abnormally hyperphosphorylated NFs into neurofibrillary tangles and extensive neuronal loss are the two major characteristics[1,2,3].Neurofilaments (NFs) are the intermediate filaments (10 nm diameter) and the most abundant cytoskeletal components, which are assembled from three NF subunits, termed light (NF-L), medium (NF-M) and heavy (NF-H) chains[4]. Our previous observations that phosphorylation of NFs was inversely regulated by O-GlcNAcylation along with NFs decreased O-GlcNAcylation in AD brain suggest that decrease of O-GlcNAcylation may contributed to the hyperphosphorylation of NFs in neurodegeneration. The proteins O-GlcNAcylation level is regulated dynamically by O-GlcNAc transferase (OGT) and β-N-acetylglucosaminidase (O-GlcNAcase, OGA). The decrease of O-GlcNAcylation by alloxan, an OGT inhibitor, and increase by NAG-thiazolines (NAG-Ae), an O-GlcNAcase inhibitor were tested to investigate the effects of O-GlcNAc alteration on AD like neurodegeneration in SK-N-SH cells. It was observed that both abnormal phosphorylation of NFs in cell bodies and apoptosis induced by alloxan treatment can be resisted by pretreatment or simultaneous treatment with appropriate NAG-Ae. Conclusion. These results demonstrated that increasing O-GlcNAc with NAG-Ae protected AD like neurodegeneration from NFs hyperphosphorylation and the cell loss, suggesting the role of O-GlcNAc in the pathogenesis and therapy of AD
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