title: Impaired eukaryotic translation initiation factor 2B activity specifically in oligodendrocytes reproduces the pathology of vanishing white matter disease in mice.
abstract: Vanishing white matter disease (VWMD) is an inherited autosomal-recessive hypomyelinating disease caused by mutations in eukaryotic translation initiation factor 2B (eIF2B). eIF2B mutations predominantly affect the brain white matter, and the characteristic features of VWMD pathology include myelin loss and foamy oligodendrocytes. Activation of pancreatic endoplasmic reticulum kinase (PERK) has been observed in oligodendrocytes in VWMD. PERK activation in response to endoplasmic reticulum stress attenuates eIF2B activity by phosphorylating eIF2α, suggesting that impaired eIF2B activity in oligodendrocytes induced by VWMD mutations or PERK activation exploit similar mechanisms to promote selective white matter pathology in VWMD. Using transgenic mice that allow for temporally controlled activation of PERK specifically in oligodendrocytes, we discovered that strong PERK activation in oligodendrocytes during development suppressed eIF2B activity and reproduced the characteristic features of VWMD in mice, including hypomyelinating phenotype, foamy oligodendrocytes, and myelin loss. Notably, impaired eIF2B activity induced by PERK activation in oligodendrocytes of fully myelinated adult mice had minimal effects on morphology or function. Our observations point to a cell-autonomous role of impaired eIF2B activity in myelinating oligodendrocytes in the pathogenesis of VWMD.
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
authors.forename: Xiaosha
authors.initials: X
authors.lastname: Pang
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
authors.forename: Guangcun
authors.initials: G
authors.lastname: Huang
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Jamison
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and.
authors.forename: Jingye
authors.initials: J
authors.lastname: Fang
authors.affiliation: University of Cambridge, Cambridge Institute of Medical Research and NIHR Cambridge Biomedical Research Centre, Cambridge, CB20XY, United Kingdom.
authors.forename: Heather P
authors.identifier: http://orcid.org/0000-0002-7359-7974
authors.initials: HP
authors.lastname: Harding
authors.affiliation: University of Cambridge, Cambridge Institute of Medical Research and NIHR Cambridge Biomedical Research Centre, Cambridge, CB20XY, United Kingdom.
authors.forename: David
authors.initials: D
authors.lastname: Ron
authors.affiliation: Department of Neuroscience, and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, and linw@umn.edu.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Lin
mesh_terms: D000818:Animals; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism; D056784:Leukoencephalopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D009186:Myelin Sheath / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism* / Q000473:pathology; D009928:Organ Specificity; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D020717:Eukaryotic Initiation Factor-2B; D019892:eIF-2 Kinase
keywords: eIF2B mutations; hypomyelination; oligodendrocyte; pancreatic endoplasmic reticulum kinase; vanishing white matter disease