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EIF2B activator prevents neurological defects caused by a chronic integrated stress response.

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.

SUBMITTER: Wong YL

PROVIDER: S-EPMC6326728 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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

Wong Yao Liang YL LeBon Lauren L Basso Ana M AM Kohlhaas Kathy L KL Nikkel Arthur L AL Robb Holly M HM Donnelly-Roberts Diana L DL Prakash Janani J Swensen Andrew M AM Rubinstein Nimrod D ND Krishnan Swathi S McAllister Fiona E FE Haste Nicole V NV O'Brien Jonathon J JJ Roy Margaret M Ireland Andrea A Frost Jennifer M JM Shi Lei L Riedmaier Stephan S Martin Kathleen K Dart Michael J MJ Sidrauski Carmela C

eLife 20190109

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 nerv ...[more]

PMID: 30624206

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Project description:Purpose: 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 performed RNA-seq analysis of cerebellum collected from mice harboring a homozygous point mutation in eIF2B5 (HO R191H), a mutation that causes a severe form of VWM in humans and compared gene expression to wildtype age-matched littermates to identify transcriptomic differences at early, mid and late time points during disease progression. We also performed RNA-seq on cerebellum collected from animals treated with the eIF2B activator 2BAct for 1 month to determine to what extent small molecule treatment could normalize the VWM transcriptome. Methods: Samples were collected at 2, 5, and 7 months of age. In addition, HO R191H and WT mice treated with and without with the eIF2B activator 2BAct for 1 month were profiled. RNA-seq libraries were prepared using purified RNA isolated from frozen tissue using the RNeasy Mini kit. RNA quality and concentration were assayed using a Fragment Analyzer instrument. RNA-seq libraries were prepared using the TruSeq Stranded Total RNA kit paired with the Ribo-Zero rRNA removal kit. Libraries were sequenced on an Illumina HiSeq 4000 instrument. For the experiment comparing different ages, N = 3 males/genotype/time point. For the 4-week 2BAct treatment experiment, N = 3 females/condition. Conclusions: HO R191H mutant brains show an elevated gene expression signature of the Integrated Stress Reponse in mice as early as 2 months, preceding the appearance of overt pathology in these animals. The expression of the ISR-related genes does not significantly increases at 5 months and 7 months of age. One month of treatment with 2BAct completely prevented the expression of ISR-related in genes in 2 month old animals.

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EIF2B activator prevents neurological defects caused by a chronic integrated stress response.

Publications

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

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