Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
  • Current Issue
  • Past Issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • 100th Anniversary of Insulin's Discovery (Jan 2021)
    • Hypoxia-inducible factors in disease pathophysiology and therapeutics (Oct 2020)
    • Latency in Infectious Disease (Jul 2020)
    • Immunotherapy in Hematological Cancers (Apr 2020)
    • Big Data's Future in Medicine (Feb 2020)
    • Mechanisms Underlying the Metabolic Syndrome (Oct 2019)
    • Reparative Immunology (Jul 2019)
    • View all review series ...
  • Viewpoint
  • Collections
    • Recently published
    • In-Press Preview
    • Commentaries
    • Concise Communication
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • Recently published
  • In-Press Preview
  • Commentaries
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Alerts
  • Advertising/recruitment
  • Subscribe
  • Contact
Astrocytes are central in the pathomechanisms of vanishing white matter
Stephanie Dooves, … , Vivi M. Heine, Marjo S. van der Knaap
Stephanie Dooves, … , Vivi M. Heine, Marjo S. van der Knaap
Published March 14, 2016
Citation Information: J Clin Invest. 2016;126(4):1512-1524. https://doi.org/10.1172/JCI83908.
View: Text | PDF
Research Article Neuroscience

Astrocytes are central in the pathomechanisms of vanishing white matter

  • Text
  • PDF
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

Stephanie Dooves, Marianna Bugiani, Nienke L. Postma, Emiel Polder, Niels Land, Stephen T. Horan, Anne-Lieke F. van Deijk, Aleid van de Kreeke, Gerbren Jacobs, Caroline Vuong, Jan Klooster, Maarten Kamermans, Joke Wortel, Maarten Loos, Lisanne E. Wisse, Gert C. Scheper, Truus E.M. Abbink, Vivi M. Heine, Marjo S. van der Knaap

×

Figure 1

Generation of VWM mouse models.

Options: View larger image (or click on image) Download as PowerPoint
Generation of VWM mouse models.
(A) 2b5ho mice were generated by introdu...
(A) 2b5ho mice were generated by introducing a construct into the Eif2b5 gene locus consisting of exons 4–6, including a point mutation in exon 4. (B) 2b4ho mice were generated by introducing a construct into the Eif2b4 gene locus consisting of exons 12 and 13, including a point mutation in exon 13. (C) Kaplan-Meier graph shows the reduced lifespan of VWM mutant mice, with an average survival of 19 months for 2b4ho mice (n = 9); 8 months for 2b5ho mice (n = 19); 4 months for 2b42b5he/ho mice (n = 12); and 3 weeks for 2b4ho2b5ho mice (n = 6). (D) Staining for MBP showed vacuolization of the cerebellar white matter in 7-month-old 2b5ho, 4-month-old 2b42b5he/ho, and P21 2b4ho2b5ho mice, but not in 7-month-old WT mice. Scale bars: 50 μm. (E) The distribution of axonal diameters was skewed to the smaller diameters in 2b5ho and 2b42b5he/ho mice (n = 92 WT mice; n = 100 2b5ho mice; n = 91 2b42b5he/ho mice). Immunostainings are representative images from at least 3 experiments.
Follow JCI:
Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts