Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro

Lisanne E. Wisse, Timo J. ter Braak, Malu-Clair van de Beek, Carola G. M. van Berkel, Joke Wortel, Vivi M. Heine, Chris G. Proud, Marjo S. van der Knaap, Truus E. M. Abbink

Research output: Contribution to journalArticleAcademicpeer-review

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 (2b5 ho ), 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- A nd 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.
Original languageEnglish
Article number3773
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - 2018

Cite this

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title = "Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro",
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 (2b5 ho ), 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- A nd 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.",
author = "Wisse, {Lisanne E.} and {ter Braak}, {Timo J.} and {van de Beek}, Malu-Clair and {van Berkel}, {Carola G. M.} and Joke Wortel and Heine, {Vivi M.} and Proud, {Chris G.} and {van der Knaap}, {Marjo S.} and Abbink, {Truus E. M.}",
year = "2018",
doi = "10.1038/s41598-018-21885-x",
language = "English",
volume = "8",
journal = "Scientific Reports",
issn = "2045-2322",
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Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro. / Wisse, Lisanne E.; ter Braak, Timo J.; van de Beek, Malu-Clair; van Berkel, Carola G. M.; Wortel, Joke; Heine, Vivi M.; Proud, Chris G.; van der Knaap, Marjo S.; Abbink, Truus E. M.

In: Scientific Reports, Vol. 8, No. 1, 3773, 2018.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro

AU - Wisse, Lisanne E.

AU - ter Braak, Timo J.

AU - van de Beek, Malu-Clair

AU - van Berkel, Carola G. M.

AU - Wortel, Joke

AU - Heine, Vivi M.

AU - Proud, Chris G.

AU - van der Knaap, Marjo S.

AU - Abbink, Truus E. M.

PY - 2018

Y1 - 2018

N2 - 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 (2b5 ho ), 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- A nd 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.

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