title: Endoplasmic reticulum stress intolerance in EIF2B3 mutant oligodendrocytes is modulated by depressed autophagy.
abstract: OBJECTIVE
  Eukaryotic translation initiation factor 2B (eIF2B) is an essential factor for the initiation of protein synthesis. Mutations in eIF2B encoded by EIF2B1-5 cause a lethal leukoencephalopathy--vanishing white matter disease (VWM). Previous studies have suggested that an improper activated unfolded protein response (UPR) after endoplasmic reticulum stress (ERS) contributed to the pathogenesis of the disease. Autophagy, an important compensatory pathway after ERS, was analyzed in this study.
  
  
  METHODS
  To determine the tolerance differences to ERS, cell viability and apoptosis rates were detected in oligodendrocyte cell lines transfected with EIF2B3-c.1037T>C or the wild type. Autophagy flux was measured between groups. Autophagy inducers and inhibitors were used to identify the role of autophagy in the mutant oligodendrocytes.
  
  
  RESULTS
  We confirmed that oligodendrocytes with mutant EIF2B3 was less tolerant to ERS than the wild type, with decreased cell viability and increased apoptosis rates. Autophagy flux was depressed in mutant oligodendrocytes under baseline condition and after ERS stimulation. Reduced expression of autophagy related gene (Atg) 3 and Atg 7 were involved in the depression of autophagy flux. The mutant oligodendrocytes pretreated with autophagy inducers showed stable cell viability and decreased apoptosis despite ERS induction, whereas the autophagy inhibitors aggravated cell apoptosis and viability declination.
  
  
  CONCLUSIONS
  Oligodendrocytes transfected with mutant EIF2B3 was less tolerant to ERS than the wild type. Depressed autophagy flux was observed in the mutant cells at baseline and after ERS stimulation. Improperly depressed autophagy played a role in the susceptibility to ERS in EIF2B3 mutant oligodendrocytes.
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Na
authors.initials: N
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Lifang
authors.initials: L
authors.lastname: Dai
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Yuwu
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Jingmin
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Neurology, Peking University First Hospital, Beijing 100034, China.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Hao
authors.affiliation: Lab of Electron Microscopy, Peking University First Hospital, Beijing 100034, China.
authors.forename: Yali
authors.initials: Y
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Xuerong
authors.initials: X
authors.lastname: Leng
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Zang
authors.affiliation: Department of Pediatrics, Peking University First Hospital, Beijing 100034, China. Electronic address: dryewu@263.net.
authors.forename: Ye
authors.initials: Y
authors.lastname: Wu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001343:Autophagy / Q000235:genetics* / Q000502:physiology; D002460:Cell Line; D002470:Cell Survival / Q000235:genetics; D059865:Endoplasmic Reticulum Stress / Q000235:genetics / Q000502:physiology; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics* / Q000378:metabolism; D009154:Mutation; D009836:Oligodendroglia / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D014157:Transcription Factors
keywords: Autophagy; EIF2B3; Endoplasmic reticulum stress (ERS); Oligodendrocyte; Vanishing white matter disease (VWM)