eIF2B activator prevents neurological defects caused by a chronic integrated stress response

ELife
Yao Liang WongCarmela Sidrauski

Abstract

The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.

References

Oct 1, 1988·Annals of Neurology·D N BlackE Reece
Apr 25, 1986·Cell·P P Mueller, A G Hinnebusch
Mar 1, 1994·Annals of Neurology·R SchiffmannC R Kaneski
Apr 1, 1997·Neurology·M S van der KnaapJ Valk
Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·O AlterD Botstein
Sep 27, 2002·Annals of Neurology·Anne FogliRaphael Schiffmann
Oct 1, 1953·Journal of Neuropathology and Experimental Neurology·H KLUVER, E BARRERA
Apr 1, 2004·European Journal of Human Genetics : EJHG·Anne FogliOdile Boespflug-Tanguy
Jul 28, 2004·Proceedings of the National Academy of Sciences of the United States of America·Krishna M Vattem, Ronald C Wek
Feb 22, 2005·Nature Medicine·Jörg DietrichChristoph Pröschel
Sep 6, 2005·Journal of Neuropathology and Experimental Neurology·J Patrick van der VoornMarjo S van der Knaap
Mar 21, 2006·Analytical Biochemistry·Michael FlagellaYuling Luo
Apr 25, 2006·Lancet Neurology·Marjo S van der KnaapGert C Scheper
Jul 11, 2006·Journal of Neuropathology and Experimental Neurology·Barbara van KollenburgMarjo S van der Knaap
Dec 7, 2007·The Journal of Biological Chemistry·Yujiro WatataniYuji Takahashi
Apr 23, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Elisa DominguezMichel Pohl
Dec 16, 2010·Journal of Neuropathology and Experimental Neurology·Marianna BugianiMarjo S van der Knaap
Dec 25, 2010·Cell·Edward L HuttlinSteven P Gygi
Jul 23, 2011·Physiological Research·M KippC Beyer
May 15, 2012·Molecular Cell·Akiko YanagiyaNahum Sonenberg
Jul 21, 2012·Cold Spring Harbor Perspectives in Biology·Alan G Hinnebusch, Jon R Lorsch
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Nov 28, 2013·Bioinformatics·Ernest TurroSimon Tavaré
Dec 18, 2013·Seminars in Pediatric Neurology·Karen S Carvalho
Jul 25, 2014·JAMA : the Journal of the American Medical Association·Robert W TaylorPatrick F Chinnery
Sep 5, 2014·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Ye ZhangJian Qian Wu
Jul 19, 2015·Mammalian Genome : Official Journal of the International Mammalian Genome Society·Jonathan M Mudge, Jennifer Harrow

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Citations

May 28, 2019·Neuromolecular Medicine·Melisa HerreroOrna Elroy-Stein
Jan 9, 2020·Journal of Neuropathology and Experimental Neurology·Sarah BondKelly L Jordan-Sciutto
Oct 7, 2019·Journal of Neurochemistry·Mika Terumitsu-TsujitaHironaka Igarashi
Jun 3, 2020·Journal of Biochemistry·Ryan HoustonYusuke Sekine
Jan 23, 2020·International Journal of Molecular Sciences·Willy RoqueFreddy Romero
Aug 15, 2020·Frontiers in Molecular Biosciences·Anne E J Hillen, Vivi M Heine
Oct 23, 2019·Neural Regeneration Research·Wensheng Lin, Sarrabeth Stone
Aug 28, 2020·The Biochemical Journal·Karthik MohanrajAgnieszka Chacinska
Jul 20, 2019·Nature Chemical Biology·Claudio HetzJohn B Patterson
Dec 17, 2019·Journal of Neurodevelopmental Disorders·Amena Smith FineAli Fatemi
Oct 7, 2020·Annual Review of Cell and Developmental Biology·Giovanna R MallucciDavid C Rubinsztein
Aug 14, 2019·Annals of Clinical and Translational Neurology·Truus E M AbbinkMarjo S van der Knaap
Apr 25, 2020·Science·Mauro Costa-Mattioli, Peter Walter
Sep 6, 2020·The Journal of Biological Chemistry·Julia M D Grandjean, R Luke Wiseman
Jan 13, 2021·Molecular Genetics & Genomic Medicine·Inna SlynkoMarjo S van der Knaap
Nov 19, 2020·Pharmacological Reviews·Muhammad Saad YousufTheodore J Price
Dec 15, 2019·Molecular Cell·Sara K Young-BairdThomas E Dever
Mar 24, 2020·Biochemistry·Assen Marintchev, Takuhiro Ito
Mar 4, 2021·Biomolecules·Talya ShachamGerardo Z Lederkremer
Aug 5, 2019·Trends in Pharmacological Sciences·Vicente Gonzalez-TeuberClaudio Hetz
May 12, 2021·Proceedings of the National Academy of Sciences of the United States of America·Satoshi WatanabeAlexander V Misharin
Jun 29, 2021·Journal of Parkinson's Disease·Vera Kovaleva, Mart Saarma
Jul 27, 2021·Seminars in Cell & Developmental Biology·Mauricio M Oliveira, Eric Klann
Sep 1, 2021·Wiley Interdisciplinary Reviews. RNA·Alyssa M EnglishStephanie L Moon

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Methods Mentioned

BETA
nucleotide
GTPase
RNA-seq
aminoacylation
scRNA-seq
column chromatography
reverse phase chromatography
PCR
chip

Software Mentioned

Prism
HALO
Cell Ranger
SCIEX
Clustering by Inferred Co - Expression ( CLIC )
R Core
GSEA
fgsea R package
R
STAR aligner

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