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EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy

Nature Medicine volume 11, pages 277–283 (2005)Cite this article

Abstract

Vanishing white matter disease (VWM) is a heritable leukodystrophy linked to mutations in translation initiation factor 2B (eIF2B). Although the clinical course of this disease has been relatively well described, the cellular consequences of EIF2B mutations on neural cells are unknown. Here we have established cell cultures from the brain of an individual with VWM carrying mutations in subunit 5 of eIF2B (encoded by EIF2B5). Despite the extensive demyelination apparent in this VWM patient, normal-appearing oligodendrocytes were readily generated in vitro. In contrast, few GFAP-expressing (GFAP+) astrocytes were present in primary cultures, induction of astrocytes was severely compromised, and the few astrocytes generated showed abnormal morphologies and antigenic phenotypes. Lesions in vivo also lacked GFAP+ astrocytes. RNAi targeting of EIF2B5 severely compromised the induction of GFAP+ cells from normal human glial progenitors. This raises the possibility that a deficiency in astrocyte function may contribute to the loss of white matter in VWM leukodystrophy.

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Figure 1: VWM patient–derived CC cells express oligodendrocyte lineage markers.
Figure 2: Lineage marker–negative, VWM patient–derived VZ cultures are capable of generating neurons, oligodendrocytes and astrocytes.
Figure 3: VWM patient–derived astrocytes show an unusual morphology.
Figure 4: Antisense targeting of EIF2B5 in hGPC leads to an impaired generation of GFAP+ astrocytes.

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Acknowledgements

We thank J. Powers for providing support and access to patient samples, H. Land for discussions and L. Silver for technical assistance. This work was supported by grants from the Children's Neurobiological Solutions Foundation (to M.M.-P. and M.N.), the Multiple Sclerosis Society of Canada (to M.M.-P. and M.N.), and the US National Institutes of Health (NS047411 to C.P., NS42820 to M.M.-P. and C.P., and HD39702 to M.N.). J.D. is a fellow of the Wilmot Cancer Foundation.

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Authors and Affiliations

  1. Department of Biomedical Genetics, Aab Institute, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Jörg Dietrich, Michelle Lacagnina, David Gass, Margot Mayer-Pröschel, Mark Noble & Christoph Pröschel

  2. Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Eric Richfield

  3. Environmental and Occupational Health Sciences Institute, UMDNJ-Robert Wood Johnson Medical School, 170 Frelinghuysen Road, Piscataway, 08854, New Jersey, USA

    Eric Richfield

  4. Department of Neurology, University of Rochester School of Medicine and Dentistry, 601 Elmwood Avenue, Rochester, 14642, New York, USA

    Carlos Torres

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Supplementary information

Supplementary Fig. 1

Paucity of GFAP+ astrocytes in demyelinating lesions of a CACH/VWM patient with known mutations in the translation initation factor subunit eIF2B5. (PDF 260 kb)

Supplementary Fig. 2

CACH/VWM disease cells are responsive to BMP-4. (PDF 207 kb)

Supplementary Fig. 3

Comparison of GFAP expression in cerebral white matter sections derived from patients with different underlying neurological diseases affecting white matter tracts. (PDF 327 kb)

Supplementary Fig. 4

RNAi inhibition of eIF2B5 expression. (PDF 89 kb)

Supplementary Table 1

Oligodeoxynucleotides used for the construction of RNAi expression plasmids targeting different regions of human eIF2B5 (PDF 21 kb)

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Dietrich, J., Lacagnina, M., Gass, D. et al. EIF2B5 mutations compromise GFAP+ astrocyte generation in vanishing white matter leukodystrophy. Nat Med 11, 277–283 (2005). https://doi.org/10.1038/nm1195

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