科研之友
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摘要
Mechanistic link of protein hypo-O-GIcNAcylation to the pathogenesis of Alzheimer's disease (AD) remains unclear. Here, we found that S-nitrosylation of O-linked N-acetylglucosaminyltransferase (SNO-OGT) was induced by beta-amyloid peptide (A beta) exposure to SK-N-MC and SK-N-SH human neuroblastoma cells. Subsequently, AP-induced SNO-OGT led to protein hypo-O-GlcNAcylation globally including tau hypo-O-GIcNAcylation. Our results support that underlying mechanism for induction of SNO-OGT comprises the concerted action of AP triggered Ca2+ entry into cells and nNOS-catalyzed NO production. Intriguingly, OGT was found to be associated with nNOS and its association was enhanced during Ap, treatment In parallel with SNO-OGT-mediated tau hypo-O-GlcNAcylation, All, led to SNO-Akt-mediated GSK3p activation for tau phosphorylation, suggesting that tau hyperphosphorylation is established by synergistic connection between SNO-OGT and GSK3 beta activation. We also observed that A beta-neurotoxicity including both reactive oxygen species (ROS) production and cell death was amplified with DON treatment, whereas it was restored by PUGNAc treatment, GlcNH(2) treatment or OGT overexpression. Early rime-course A beta-monitoring assay revealed that premaintained hyper-O-GIcNAcylation inside cells blocked not only AP-triggered Ca2+ entry into cells but also induction of SNO-OGT and SNO-Alit. Together, these findings suggest that induction of SNO-OGT by Ap exposure is a pathogenic mechanism to cause cellular hypo-OGIcNAcylation by which Ap, neurotoxicity is executed, and conversely, hyper-O-GlcNAcylation within cells can defend against All neurotoxicity. Furthermore, our Cys mapping demonstrates that cysteine-nitric oxide (Cys-NO) linkages in SNO-OGT occur at triple Cys845, Cys921, and Cys965 residues in C-terminal catalytic domain (C-CAT), suggesting that Cys-NO linkage triplet in SNO-OGT is associated with null OGT activity.
- 出版日期2016-5
