title: The unfolded protein response in vanishing white matter disease.
abstract: Leukoencephalopathy with vanishing white matter (VWM) is an autosomal-recessive disorder in which febrile infections may provoke major neurologic deterioration. Characteristic pathologic findings include cystic white matter degeneration, foamy oligodendrocytes, dysmorphic astrocytes and oligodendrocytes, oligodendrocytosis, and apoptotic losses of oligodendrocytes. VWM is caused by mutations in eukaryotic initiation factor (eIF) 2B (eIF2B). eIF2B plays an important role in the regulation of protein synthesis. Mutant eIF2B may impair the ability of cells to regulate protein synthesis in response to stress and perhaps even under normal conditions. An overload of misfolded proteins in the endoplasmic reticulum activates the unfolded protein response (UPR), a compensatory mechanism that inhibits synthesis of new proteins and induces both prosurvival and proapoptotic signals. We have studied the activation of the UPR in VWM through the immunohistochemical expression of its upstream components PERK and phosphorylated eIF2alpha (eIF2alphaP) and combined immunohistochemical and Western blot analysis of the downstream effector proteins activating transcription factor-4 (ATF4) and C/EBP homologous protein (CHOP) in 4 VWM brains and 3 age-matched controls. We demonstrate activation of the UPR in glia of patients with VWM. Our findings may point to a possible explanation for the dysmorphic glia, the increased numbers of oligodendrocytes, and the apoptotic loss of oligodendrocytes in VWM.
authors.affiliation: Department of Pediatrics/Child Neurology, VU University Medical Center, Amsterdam, The Netherlands. jp.vandervoorn@vumc.nl
authors.forename: J Patrick
authors.initials: JP
authors.lastname: van der Voorn
authors.forename: Barbara
authors.initials: B
authors.lastname: van Kollenburg
authors.forename: Gesina
authors.initials: G
authors.lastname: Bertrand
authors.forename: Keith
authors.initials: K
authors.lastname: Van Haren
authors.forename: Gert C
authors.initials: GC
authors.lastname: Scheper
authors.forename: James M
authors.initials: JM
authors.lastname: Powers
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
mesh_terms: D051701:Activating Transcription Factor 4; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D001927:Brain Diseases / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D004591:Electrophoresis, Polyacrylamide Gel; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D009154:Mutation; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis / Q000235:genetics; D017510:Protein Folding; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: D051701:Activating Transcription Factor 4; D022762:CCAAT-Enhancer-Binding Proteins; D015852:Eukaryotic Initiation Factor-2; D051742:Transcription Factor CHOP; D014157:Transcription Factors; D019892:eIF-2 Kinase; C497109:ATF4 protein, human; C497249:DDIT3 protein, human