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Elife. 2019 Jan 9;8. pii: e42940. doi: 10.7554/eLife.42940.

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

Author information

1
Calico Life Sciences LLC, South San Francisco, United States.
2
AbbVie, North Chicago, United States.
#
Contributed equally

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.

KEYWORDS:

biochemistry; chemical biology; disease models; mouse; neurodegeneration; neuroscience

Conflict of interest statement

YW, LL, NR, SK, FM, NH, JO, MR, AI employee of Calico Life Sciences LLC at the time the study was conducted and has no other competing financial interests to declare, AB, KK, AN, HR, DD, JP employee of AbbVie at the time the study was conducted and has no other competing financial interests to declare. AS, SR No competing interests declared, JF, LS, MD employee of AbbVie and is listed as an inventor on a patent application WO2017193063 describing 2BAct, KM, CS employee of Calico Life Sciences and is listed as an inventor on a patent application WO2017193063 describing 2BAct

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