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

Author:

Wong Yao Liang1ORCID,LeBon Lauren1ORCID,Basso Ana M2,Kohlhaas Kathy L2,Nikkel Arthur L2,Robb Holly M2,Donnelly-Roberts Diana L2,Prakash Janani2,Swensen Andrew M2,Rubinstein Nimrod D1,Krishnan Swathi1,McAllister Fiona E1,Haste Nicole V1,O'Brien Jonathon J1ORCID,Roy Margaret1,Ireland Andrea1,Frost Jennifer M2,Shi Lei2,Riedmaier Stephan2,Martin Kathleen1,Dart Michael J2,Sidrauski Carmela1ORCID

Affiliation:

1. Calico Life Sciences LLC, South San Francisco, United States

2. AbbVie, North Chicago, United States

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.

Funder

Calico Life Sciences LLC

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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