Abstract
Vanishing white matter (VWM) is a genetic childhood white matter disorder, characterized by chronic as well as episodic, stress provoked, neurological deterioration. Treatment is unavailable and patients often die within a few years after onset. VWM is caused by recessive mutations in the eukaryotic initiation factor 2B (eIF2B). eIF2B regulates protein synthesis rates in every cell of the body. In normal cells, various types of cellular stress inhibit eIF2B activity and induce the integrated stress response (ISR). We have developed a VWM mouse model homozygous for the pathogenic Arg191His mutation in eIF2Bε (2b5ho), representative of the human disease. Neuropathological examination of VWM patient and mouse brain tissue suggests that astrocytes are primarily affected. We hypothesized that VWM astrocytes are selectively hypersensitive to ISR induction, resulting in a heightened response. We cultured astrocytes from wildtype and VWM mice and investigated the ISR in assays that measure transcriptional induction of stress genes, protein synthesis rates and cell viability. We investigated the effects of short- and long-term stress as well as stress recovery. We detected congruent results amongst the various assays and did not detect a hyperactive ISR in VWM mouse astrocytes.
Highlights
Vanishing white matter (VWM) is a genetic childhood white matter disorder, characterized by chronic as well as episodic, stress provoked, neurological deterioration
To further address this issue, we investigated selective activation of the integrated stress response (ISR) in 2b5ho astrocytes using four additional compounds (CCT020312, BEPP, BTdCPU, halofuginone) that were recently described as ISR inducers[37,38,39,40]
We previously found that astrocytes are likely the cells that are primarily affected cells in VWM12
Summary
Vanishing white matter (VWM) is a genetic childhood white matter disorder, characterized by chronic as well as episodic, stress provoked, neurological deterioration. Neuropathological examination of VWM patient and mouse brain tissue suggests that astrocytes are primarily affected. We cultured astrocytes from wildtype and VWM mice and investigated the ISR in assays that measure transcriptional induction of stress genes, protein synthesis rates and cell viability. Astrocytes and oligodendrocytes (together the “macroglia” or, in short, the “glia”) are selectively affected. VWM patients have bi-allelic recessive mutations in any of the five genes encoding the subunits of the eukaryotic translation factor 2B (eIF2B)[10,11].
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