The Role of O-GlcNAcylation in Alzheimer’s Disease Pathogenesis

다국어 초록 (Multilingual Abstract)

Since conventional secretory pathway from ER to Golgi is involved in many essential functions of a cell, it is an important to understand how transport vesicles are regulated. The pathway is initiated by ER’s making transport vesicles at ER exit sites (ERES) with specific coat protein complexes such as COPII vesicles. Our previous study showed that O-GlcNAcylation (O-GlcNAc) on Sec31A, a main component for COPII vesicle, accelerates the anterograde transport of vesicles in ER-Golgi networks. In the present study, we focused on the effect of Ab, a crucial factor in the pathogenesis of Alzheimer’s disease (AD), on the formation of COPII vesicles at ERES. Ab-induced disrupted intracellular calcium levels affected the formation of COPII vesicles at ERES through O-GlcNAcylation of Sec31A in neuronal cells. In addition, Ab caused Golgi fragmentation which was rescued by up-regulation of O-GlcNAcylation using Thiamet G, an OGA inhibitor. Overall, Ab impaired ERES formation through altered Sec31A O-GlcNAcylation triggered by disruption of intracellular calcium homeostasis, suggesting that protection of ERES or Sec31 O-GlcNAcylation may be a promising novel avenue for the development of AD therapeutics.