title: A point mutation in translation initiation factor 2B leads to a continuous hyper stress state in oligodendroglial-derived cells.
abstract: BACKGROUND
  Mutations in eukaryotic translation initiation factor 2B (eIF2B) cause Childhood Ataxia with CNS Hypomyelination (CACH), also known as Vanishing White Matter disease (VWM). The disease is manifested by loss of brain myelin upon physiological stress. In a previous study, we showed that fibroblasts isolated from CACH/VWM patients are hypersensitive to pharmacologically-induced endoplasmic reticulum (ER) stress. Since brain cells from affected individuals are not available for research, we wished to assess the effect of eIF2B mutation on oligodendroglial-derived cells.
  
  
  RESULTS
  A rat oligodendroglial-derived cell line was used for a stable knock-down of eIF2B5 followed by stable expression of mutated eIF2B5(R195H) cDNA. In response to a pharmacological ER-stress agent, eIF2B5(R195H) expressing cells exhibited heightened ER-stress response demonstrated by hyper induction of ATF4, GADD34, Bip, PDIA1, PDIA3, PDIA4 and PDIA6 proteins. Moreover, even in the absence of a pharmacological stress agent, eIF2B5(R195H)-expressing cells exhibited high basal levels of ATF4, GADD34 and ER-associated Bip, PDIA1 and PDIA3.
  
  
  CONCLUSIONS
  The data provide evidence that oligodendroglial-derived cells expressing a mutated eIF2B constantly use their stress response mechanism as an adaptation mean in order to survive. The current study is the first to demonstrate the effects of eIF2B5 mutation on ER homeostasis in oligodendroglial-derived cells.
authors.affiliation: Department of Cell Research & Immunology, George S. Wise Faculty of Life Sciences, Tel-Aviv University, Tel-Aviv, Israel.
authors.forename: Liraz
authors.initials: L
authors.lastname: Kantor
authors.forename: Dalia
authors.initials: D
authors.lastname: Pinchasi
authors.forename: Michelle
authors.initials: M
authors.lastname: Mintz
authors.forename: Yetrib
authors.initials: Y
authors.lastname: Hathout
authors.forename: Adeline
authors.initials: A
authors.lastname: Vanderver
authors.forename: Orna
authors.initials: O
authors.lastname: Elroy-Stein
mesh_terms: D000818:Animals; D001259:Ataxia / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D017931:DNA Primers / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000378:metabolism; D020717:Eukaryotic Initiation Factor-2B / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D008959:Models, Neurological; D016297:Mutagenesis, Site-Directed; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D017354:Point Mutation; D020543:Proteome; D051381:Rats; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D014162:Transfection
chemical_list: D017931:DNA Primers; D020717:Eukaryotic Initiation Factor-2B; D020543:Proteome; D011994:Recombinant Proteins