Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

Here, we investigated how persistent ISR activation impacts cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a knock-in mouse line carrying the pathogenic allele.

We found that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. Importantly, we demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral orthologue of PPP1R15B, revealing new molecular and structural insights as a potent pan-ISR inhibitor.