2. Academic Validation
  3. eIF2B activator prevents neurological defects caused by a chronic integrated stress response

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

  • Elife. 2019 Jan 9;8:e42940. doi: 10.7554/eLife.42940.
Yao Liang Wong  # 1,  Lauren LeBon 1,  Ana M Basso 2,  Kathy L Kohlhaas 2,  Arthur L Nikkel 2,  Holly M Robb 2,  Diana L Donnelly-Roberts 2,  Janani Prakash 2,  Andrew M Swensen 2,  Nimrod D Rubinstein 1,  Swathi Krishnan 1,  Fiona E McAllister 1,  Nicole V Haste 1,  Jonathon J O'Brien 1,  Margaret Roy 1,  Andrea Ireland 1,  Jennifer M Frost 2,  Lei Shi 2,  Stephan Riedmaier 2,  Kathleen Martin 1,  Michael J Dart 2,  Carmela Sidrauski 1
Affiliations

Affiliations

  • 1 Calico Life Sciences LLC, South San Francisco, United States.
  • 2 AbbVie, North Chicago, United States.
  • # Contributed equally.
PMID: 30624206 DOI: 10.7554/eLife.42940
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.

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