Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro
Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro
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.
Wisse, Lisanne E.
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Ter Braak, Timo J.
fc0ca255-e6cc-4579-8869-6f7b1c413f68
Van De Beek, Malu Clair
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Van Berkel, Carola G.M.
7603a118-68a1-4cc4-ad07-82af63ff4205
Wortel, Joke
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Heine, Vivi M.
c12e01d9-d85e-4750-acff-c8bc751ead96
Proud, Chris G.
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Van Der Knaap, Marjo S.
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Abbink, Truus E.M.
5b55e457-1a01-415d-97bd-a339af2283d6
1 December 2018
Wisse, Lisanne E.
cabb4886-7507-4b2c-ba05-119b802d0553
Ter Braak, Timo J.
fc0ca255-e6cc-4579-8869-6f7b1c413f68
Van De Beek, Malu Clair
a4215ba5-4795-4a6a-b4d0-a24aaa46614f
Van Berkel, Carola G.M.
7603a118-68a1-4cc4-ad07-82af63ff4205
Wortel, Joke
c3ee7f41-0570-4071-b0b0-9265042f293f
Heine, Vivi M.
c12e01d9-d85e-4750-acff-c8bc751ead96
Proud, Chris G.
5832db56-9069-4617-a80d-08b069093dba
Van Der Knaap, Marjo S.
95a7eed6-744e-4beb-8c73-43f1f37effdd
Abbink, Truus E.M.
5b55e457-1a01-415d-97bd-a339af2283d6
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. and Abbink, Truus E.M.
(2018)
Adult mouse eIF2Bϵ Arg191His astrocytes display a normal integrated stress response in vitro.
Scientific Reports, 8 (1), [3773].
(doi:10.1038/s41598-018-21885-x).
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.
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Accepted/In Press date: 23 January 2018
e-pub ahead of print date: 28 February 2018
Published date: 1 December 2018
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Local EPrints ID: 418720
URI: http://eprints.soton.ac.uk/id/eprint/418720
ISSN: 2045-2322
PURE UUID: d1cd069b-41ee-412f-bc0d-36d82dcc86d7
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Date deposited: 20 Mar 2018 17:30
Last modified: 15 Mar 2024 18:59
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Contributors
Author:
Lisanne E. Wisse
Author:
Timo J. Ter Braak
Author:
Malu Clair Van De Beek
Author:
Carola G.M. Van Berkel
Author:
Joke Wortel
Author:
Vivi M. Heine
Author:
Chris G. Proud
Author:
Marjo S. Van Der Knaap
Author:
Truus E.M. Abbink
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