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, Christopher
AU - Van Der Knaap, Marjo S.
AU - Abbink, Truus E.M.
N1 - Funding Information:
We kindly acknowledge Professor Dr. Frank Baas (Department of Genome Analysis, Amsterdam Medical Center, Amsterdam, the Netherlands) for stimulating fruitful discussions. We thank I.G. Metgod and C.M.T. Beertsen (Department of Clinical Chemistry, VU Medical Center, Amsterdam, The Netherlands) for use of the VICTOR luminescence plate reader. We thank Dr. Wiep Scheper (Department of Functional Genomics, VU University, Amsterdam, The Netherlands) for the kind gift of the ATF4 antibody. Dutch Organization for Scientific Research (ZonMw TOP grant 91211005). Dutch Brain foundation (Hersenstichting project grant BGWS2014(1)-04). The Phelps Foundation (grant 2011.040).
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/1/1
Y1 - 2018/1/1
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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85042944393&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-21885-x
DO - 10.1038/s41598-018-21885-x
M3 - Article
C2 - 29491431
AN - SCOPUS:85042944393
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 3773
ER -