DOI: 10.1101/462820Nov 5, 2018Paper

eIF2B activator prevents neurological defects caused by a chronic Integrated Stress Response

BioRxiv : the Preprint Server for Biology
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 novel 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 other disease contexts.

Methods Mentioned

BETA
RNA-seq
PCR
reverse phase chromatography
aminoacylation
GTPase
nucleotide

Software Mentioned

Prism
MMSEQ
STAR aligner
HALO
STAR
gplots
SCIEX
2BAct
MMDIFF
Analyst

Related Concepts

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