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eIF2B Mutations Cause Mitochondrial Malfunction in Oligodendrocytes

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Abstract

Vanishing white matter (VWM) disease (OMIM#306896) is an autosomal recessive neurodegenerative leukodystrophy caused by hypomorphic mutations in any of the five genes encoding the subunits of eukaryotic translation initiation factor 2B (eIF2B). The disease is manifested by loss of cerebral white matter and progressive deterioration upon exposure to environmental and physiological stressors. “Foamy” oligodendrocytes (OLG), increased numbers of oligodendrocytes precursor cells (OPC), and immature defective astrocytes are major neuropathological denominators. Our recent work using Eif2b5R132H/R132H mice uncovered a fundamental link between eIF2B and mitochondrial function. A decrease in oxidative phosphorylation capacity was observed in mutant astrocytes and fibroblasts. While an adaptive increase in mitochondria abundance corrects the phenotype of mutant fibroblasts, it is not sufficient to compensate for the high-energy demand of astrocytes, explaining their involvement in the disease. To date, astrocytes are marked as central for the disease while eIF2B-mutant OLG are currently assumed to lack a cellular phenotype on their own. Here we show a reduced capacity of eIF2B-mutant OPC isolated from Eif2b5R132H/R132H mice to conduct oxidative respiration despite the adaptive increase in their mitochondrial abundance. We also show their impaired ability to efficiently complete critical differentiation steps towards mature OLG. The concept that defective differentiation of eIF2B-mutant OPC could be a consequence of mitochondrial malfunction is in agreement with numerous studies indicating high dependency of differentiating OLG on accurate mitochondrial performance and ATP availability.

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Acknowledgements

This study was funded by the U.S.-Israel Binational Science Foundation (BSF) Grant #2009159 and by the VWM Saxby project grant to OES.

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Authors and Affiliations

  1. School of Molecular Cell Biology and Biotechnology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel

    Melisa Herrero & Orna Elroy-Stein

  2. Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel

    Shir Mandelboum & Orna Elroy-Stein

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  1. Melisa Herrero
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  2. Shir Mandelboum
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Correspondence to Orna Elroy-Stein.

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All procedures performed in studies involving animals were in accordance with the ethical standards of Tel Aviv University Animal Care Committee according to national guidelines (permit #04-17-022). This article does not contain any studies with human participants performed by any of the authors.

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Herrero, M., Mandelboum, S. & Elroy-Stein, O. eIF2B Mutations Cause Mitochondrial Malfunction in Oligodendrocytes. Neuromol Med 21, 303–313 (2019). https://doi.org/10.1007/s12017-019-08551-9

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