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.
Highlights
EIF2B is the guanine nucleotide exchange factor (GEF) for the GTPase and initiation factor eIF2 and modulation of its activity is central to regulation of protein synthesis rates in all eukaryotic cells
We synthesized 2BAct, which has a differentiated bicyclo[1.1.1]pentyl core and, unlike ISRIB, is no longer symmetric (Figure 1A). 2BAct is a highly selective eIF2B activator and exhibited similar potency to ISRIB in a cell-based reporter assay that measures integrated stress response (ISR) attenuation (Figure 1—figure supplement 1A and Supplementary file 1A). 2BAct is able to penetrate the central nervous system (CNS) and demonstrated dose-dependent oral bioavailability using an aqueous-based vehicle (Supplementary file 1B)
Our data demonstrate that a subset of astrocytes possess a basal ISR in normal mice, which is further activated when eIF2B is mutated
Summary
EIF2B is the guanine nucleotide exchange factor (GEF) for the GTPase and initiation factor eIF2 and modulation of its activity is central to regulation of protein synthesis rates in all eukaryotic cells. In a severe neurological condition called Vanishing White Matter (VWM), the genes that produce the eIF2B proteins contain mutations that make eIF2B less active. We previously showed that a range of VWM mutations destabilize the eIF2B decamer, leading to compromised GEF activity in both recombinant complexes and endogenous protein from cell lysates (Wong et al, 2018). We demonstrated that the small molecule eIF2B activator ISRIB (for ISR inhibitor) stabilized the decameric form of both wild-type (WT) and VWM mutant complexes, boosting their intrinsic activity. We showed that ISRIB attenuated ISR activation and restored protein synthesis in cells carrying VWM mutations (Wong et al, 2018). We generate an improved tool molecule and demonstrate that sustained eIF2B activation blocks maladaptive induction of the ISR and prevents all evaluated disease phenotypes in a VWM mouse model
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