Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. 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. Remarkably, DP71L reversed the cognitive and synaptic deficits across diverse conditions—including Down syndrome, Alzheimer’s disease and aging—and enhanced synaptic plasticity and memory in healthy mice. Our findings illustrate how human genetics and viral adaptations converge to unlock potential innovative therapeutic strategies for cognitive disorders.