title: Astrocytes are central in the pathomechanisms of vanishing white matter.
abstract: Vanishing white matter (VWM) is a fatal leukodystrophy that is caused by mutations in genes encoding subunits of eukaryotic translation initiation factor 2B (eIF2B). Disease onset and severity are codetermined by genotype. White matter astrocytes and oligodendrocytes are almost exclusively affected; however, the mechanisms of VWM development remain unclear. Here, we used VWM mouse models, patients' tissue, and cell cultures to investigate whether astrocytes or oligodendrocytes are the primary affected cell type. We generated 2 mouse models with mutations (Eif2b5Arg191His/Arg191His and Eif2b4Arg484Trp/Arg484Trp) that cause severe VWM in humans and then crossed these strains to develop mice with various mutation combinations. Phenotypic severity was highly variable and dependent on genotype, reproducing the clinical spectrum of human VWM. In all mutant strains, impaired maturation of white matter astrocytes preceded onset and paralleled disease severity and progression. Bergmann glia and retinal Müller cells, nonforebrain astrocytes that have not been associated with VWM, were also affected, and involvement of these cells was confirmed in VWM patients. In coculture, VWM astrocytes secreted factors that inhibited oligodendrocyte maturation, whereas WT astrocytes allowed normal maturation of VWM oligodendrocytes. These studies demonstrate that astrocytes are central in VWM pathomechanisms and constitute potential therapeutic targets. Importantly, astrocytes should also be considered in the pathophysiology of other white matter disorders.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Dooves
authors.forename: Marianna
authors.initials: M
authors.lastname: Bugiani
authors.forename: Nienke L
authors.initials: NL
authors.lastname: Postma
authors.forename: Emiel
authors.initials: E
authors.lastname: Polder
authors.forename: Niels
authors.initials: N
authors.lastname: Land
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Horan
authors.forename: Anne-Lieke F
authors.initials: AL
authors.lastname: van Deijk
authors.forename: Aleid
authors.initials: A
authors.lastname: van de Kreeke
authors.forename: Gerbren
authors.initials: G
authors.lastname: Jacobs
authors.forename: Caroline
authors.initials: C
authors.lastname: Vuong
authors.forename: Jan
authors.initials: J
authors.lastname: Klooster
authors.forename: Maarten
authors.initials: M
authors.lastname: Kamermans
authors.forename: Joke
authors.initials: J
authors.lastname: Wortel
authors.forename: Maarten
authors.initials: M
authors.lastname: Loos
authors.forename: Lisanne E
authors.initials: LE
authors.lastname: Wisse
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
authors.forename: Truus E M
authors.initials: TE
authors.lastname: Abbink
authors.forename: Vivi M
authors.initials: VM
authors.lastname: Heine
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D018920:Coculture Techniques; D004195:Disease Models, Animal; D020717:Eukaryotic Initiation Factor-2B / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056784:Leukoencephalopathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008817:Mice, Mutant Strains; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D066127:White Matter / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology
chemical_list: D020717:Eukaryotic Initiation Factor-2B