The small molecule ISRIB rescues the stability and activity of Vanishing White Matter Disease eIF2B mutant complexes

Abstract

eIF2B is a dedicated guanine nucleotide exchange factor for eIF2, the GTPase that is essential to initiate mRNA translation. The integrated stress response (ISR) signaling pathway inhibits eIF2B activity, attenuates global protein synthesis and upregulates a set of stress-response proteins. Partial loss-of-function mutations in eIF2B cause a neurodegenerative disorder called Vanishing White Matter Disease (VWMD). Previously, we showed that the small molecule ISRIB is a specific activator of eIF2B (Sidrauski et al., 2015). Here, we report that various VWMD mutations destabilize the decameric eIF2B holoenzyme and impair its enzymatic activity. ISRIB stabilizes VWMD mutant eIF2B in the decameric form and restores the residual catalytic activity to wild-type levels. Moreover, ISRIB blocks activation of the ISR in cells carrying these mutations. As such, ISRIB promises to be an invaluable tool in proof-of-concept studies aiming to ameliorate defects resulting from inappropriate or pathological activation of the ISR.

Integrated Stress Response Deregulation underlies Vanishing White Matter and is a target for therapy

“…We used ISRIB, an ISR inhibitor (15)(16)(17)(18), in VWM mice to modulate the deregulated ISR and study the impact of this modulation on the disease. ISRIB stabilizes the eIF2B complex by direct binding (16,19,20). As a consequence, ISRIB enhances eIF2B activity, which reduces the expression of ATF4 and impacts expression of the ATF4-regulated transcriptome (16,18,19).…”

“…ISRIB stabilizes the eIF2B complex by direct binding (16,19,20). As a consequence, ISRIB enhances eIF2B activity, which reduces the expression of ATF4 and impacts expression of the ATF4-regulated transcriptome (16,18,19). The compound has been successful in treatment of a prion-infected mouse model for neurodegeneration (15).…”

Structural insights into ISRIB, a memory‐enhancing inhibitor of the integrated stress response

“…Furthermore, Wong et al reported that eIF2B activation can rescue defects in GEF activity due to VWMD mutations and ameliorate disease in rodent models [22,23]. Furthermore, Wong et al reported that eIF2B activation can rescue defects in GEF activity due to VWMD mutations and ameliorate disease in rodent models [22,23].…”

“…Previous research demonstrated that VWMD mutations can lead to a decrease in GEF activity. Furthermore, Wong et al reported that eIF2B activation can rescue defects in GEF activity due to VWMD mutations and ameliorate disease in rodent models [22,23]. A particularly deleterious variant, dR483W, was dramatically restored to near full activity by ISRIB in cells.…”

Structural basis of eIF2B-catalyzed GDP exchange and phosphoregulation by the integrated stress response

“…When administered to rodents, ISRIB enhances cognition and reverses cognitive deficits due to traumatic brain injury (15) and prion-induced neurodegeneration (16). Furthermore, eIF2B activation rescues cognitive and motor function in mouse models of 65 leukoencephalopathy with vanishing white matter (VWM), a debilitating or fatal autosomal disorder associated with hundreds of mutations in all subunits of eIF2B (17,18). Remarkably, ISRIB exerts its effects without overt toxicity (12, 16) due to restoration of the cytoprotective activity of the ISR when stress levels increase (19).…”