Bergmann glia translocation: a new disease marker for vanishing white matter identifies therapeutic effects of Guanabenz treatment

S. Dooves, M. Bugiani, L. E. Wisse, T. E.M. Abbink, M. S. van der Knaap, V. M. Heine*

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Aim: Vanishing White Matter (VWM) is a devastating leucoencephalopathy without effective treatment options. Patients have mutations in the EIF2B1-5 genes, encoding the five subunits of eIF2B, a guanine exchange factor that is an important regulator of protein translation. We recently developed mouse models for VWM that replicate the human disease. To study disease improvement after treatment in these mice, it is essential to have sensitive biomarkers related to disease stage. The Bergmann glia of the cerebellum, an astrocytic subpopulation, translocate into the molecular layer in symptomatic VWM mice and patients. This study looked at the prospects of using Bergmann glia pathology as an objective disease marker for VWM. Methods: We defined a new quantitative measurement of Bergmann glia pathology in the cerebellum of VWM mice and patients. To test the sensitivity of this new marker for improvement, VWM mutant mice received long-term treatment with Guanabenz, an FDA-approved anti-hypertensive agent affecting eIF2B activity. Results: Bergmann glia translocation was significantly higher in symptomatic VWM mice and VWM patients than in controls and worsened over the disease course. Both Bergmann glia pathology and cerebellar myelin pathology improved with Guanabenz treatment in mice, showing that Bergmann glia translocation is a sensitive measurement for improvement. Conclusions: Bergmann glia translocation can be used to objectively assess effects of treatment in VWM mice. Future treatment strategies involving compounds regulating eIF2 phosphorylation might benefit VWM patients.

Original languageEnglish
Pages (from-to)391-403
Number of pages13
JournalNeuropathology and Applied Neurobiology
Volume44
Issue number4
Early online date13 May 2018
DOIs
Publication statusPublished - Jun 2018

Funding

The authors thank Gerbren Jacobs, Nienke Postma and Timo ter Braak for technical assistance, and Prof. Dr. David Rowitch and Dr. Hiroko Nobuta (UCSF, San Francisco, California, USA) for providing shiverer brain tissue. VMH is supported by ZonMw VIDI research grant 91712343, the ZonMw TAS IDB project 116005006 and E-Rare Joint Call project 9003037601. M.S.v.d.K. is supported by the NWO Spinoza grant.

FundersFunder number
NWO Spinoza
University of California, San Francisco
ZonMw91712343
Islamic Development Bank9003037601, 116005006

    Keywords

    • astrocytes
    • Bergmann glia
    • cerebellum
    • Guanabenz
    • therapy
    • Vanishing White Matter

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