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

Biol Cell. 2020 Dec;112(12):439-451. doi: 10.1111/boc.201900062. Epub 2020 Oct 25.

Abstract

Background information: Aberrant production of amyloid beta (Aβ) 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 Aβ impaired ERES through Aβ-disturbed calcium homeostasis and O-GlcNAcylation of Sec31A in neuronal cells. Furthermore, we identified that Aβ disrupted the ribbon-like structure of Golgi. Golgi fragmentation by Aβ 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 Aβ treatment.

Conclusions: This study demonstrated that Aβ 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.

Keywords: ER exit sites; Golgi fragmentation; O-GlcNAcylation; Sec31A; amyloid beta; calcium homeostasis; coat protein complex II vesicle.

MeSH terms

  • Alzheimer Disease / metabolism*
  • Amyloid beta-Peptides / metabolism*
  • Apoptosis Regulatory Proteins / metabolism*
  • COP-Coated Vesicles / metabolism
  • Calcium / metabolism*
  • Calcium-Binding Proteins / metabolism*
  • Endoplasmic Reticulum / metabolism*
  • HeLa Cells
  • Humans
  • Protein Processing, Post-Translational
  • Protein Transport
  • Vesicular Transport Proteins / metabolism*

Substances

  • Amyloid beta-Peptides
  • Apoptosis Regulatory Proteins
  • Calcium-Binding Proteins
  • PDCD6 protein, human
  • SEC31A protein, human
  • Vesicular Transport Proteins
  • Calcium