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 journalArticle

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.

LanguageEnglish
Article number3773
Pages1-9
Number of pages9
JournalScientific Reports
Volume8
Issue number1
DOIs
StatePublished - 28 Feb 2018

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Astrocytes
Eukaryotic Initiation Factor-2B
Mutation
White Matter
In Vitro Techniques
Heat-Shock Proteins
Cell Survival
Proteins
Brain

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Wisse, L. E., Ter Braak, T. J., Van De Beek, M. C., Van Berkel, C. G. M., Wortel, J., Heine, V. M., ... Abbink, T. E. M. (2018). Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro. Scientific Reports, 8(1), 1-9. [3773]. DOI: 10.1038/s41598-018-21885-x
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./ Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 1-9
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Wisse, LE, Ter Braak, TJ, Van De Beek, MC, Van Berkel, CGM, Wortel, J, Heine, VM, Proud, CG, Van Der Knaap, MS & Abbink, TEM 2018, 'Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro' Scientific Reports, vol 8, no. 1, 3773, pp. 1-9. DOI: 10.1038/s41598-018-21885-x

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, 28.02.2018, p. 1-9.

Research output: Contribution to journalArticle

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AU - Ter Braak,Timo J.

AU - Van De Beek,Malu Clair

AU - Van Berkel,Carola G.M.

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AU - Heine,Vivi M.

AU - Proud,Chris G.

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Wisse LE, Ter Braak TJ, Van De Beek MC, Van Berkel CGM, Wortel J, Heine VM et al. Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro. Scientific Reports. 2018 Feb 28;8(1):1-9. 3773. Available from, DOI: 10.1038/s41598-018-21885-x