Amyloid beta regulates ER exit sites formation through O-GlcNAcylation triggered by disrupted calcium homeostasis

Abstract

Background Information Aberrant production of amyloid beta (A beta) causes disruption of intracellular calcium homeostasis, a crucial factor in the pathogenesis of Alzheimer's disease. Calcium is required for the fusion and trafficking of vesicles. Previously, we demonstrated that Sec31A, a main component for coat protein complex II (COPII) vesicles at ER exit sites (ERES), is modulated by O-GlcNAcylation. O-GlcNAcylation, a unique and dynamic protein glycosylation process, modulates the formation of COPII vesicles. Results In this study, we observed that disrupted calcium levels affected the formation of COPII vesicles in ERES through calcium-triggered O-GlcNAcylation of Sec31A. Additionally, we found that A beta impaired ERES through A beta-disturbed calcium homeostasis and O-GlcNAcylation of Sec31A in neuronal cells. Furthermore, we identified that A beta disrupted the ribbon-like structure of Golgi. Golgi fragmentation by A beta was rescued by up-regulation of O-GlcNAcylaion levels using Thiamet G (ThiG), an O-GlcNAcase inhibitor. Additionally, we observed that the Golgi reassembly stacking proteins having a function in Golgi stacking showed attenuation at COPII vesicles following A beta treatment. Conclusions This study demonstrated that A beta impaired Sec31A targeting to ERES through altered Sec31A O-GlcNAcylation triggered by disruption of intracellular calcium homeostasis. Significance The findings of this study suggested that protection of ERES or Sec31 O-GlcNAcylation may offer a promising novel avenue for development of AD therapeutics.