Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response.

The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. We investigated how persistent ISR activation affects cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a mouse line with the pathogenic allele inserted. This variant destabilized the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. We demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral ortholog of PPP1R15B, which acted as a potent pan-ISR inhibitor. DP71L reversed the cognitive and synaptic deficits across mouse models of Down syndrome, Alzheimer's disease, and aging, and enhanced synaptic plasticity and memory in healthy mice. Editor's summary: Persistent activation of the integrated stress response (ISR) drives cognitive dysfunction across neurological disorders. Reineke et al. developed a mouse model carrying a genetic variant linked to intellectual disability that faithfully replicates human disease. Using this model, they uncovered cellular and molecular mechanisms through which chronic ISR activation impairs cognitive processing. They also characterized a viral protein that potently suppresses ISR and provided atomic-level insights into the key residues mediating function. Treatment with this protein restored cognitive function in mouse models of Down syndrome, Alzheimer's disease, and aging, all of which feature persistent ISR activation, and even enhanced memory and neuronal plasticity in healthy mice. —Stella M. Hurtley INTRODUCTION: The integrated stress response (ISR) is an evolutionarily conserved signaling network that helps cells adapt by adjusting protein production when homeostasis is disrupted. By controlling eIF2 phosphorylation, the ISR regulates general protein synthesis while selectively promoting the synthesis of adaptive proteins, allowing cells and organisms to cope with diverse environmental and physiological challenges. In the brain, the ISR evolved beyond stress management to control long-lasting changes in synaptic function and long-term memory formation. Inhibiting the ISR enhances long-term memory formation, whereas its activation impairs it. More importantly, persistent ISR activation—triggered by disruption of cellular homeostasis—is increasingly being recognized as a central mechanism underlying cognitive deficits in a wide range of neurological disorders. RATIONALE: Persistent activation of the ISR has been linked to cognitive impairments in neurodevelopmental and neurological disorders. However, the mechanisms connecting chronic ISR activity to neuronal dysfunction remain poorly understood. To address this, we focused on a naturally occurring human genetic variant in the phosphatase cofactor PPP1R15B, which activates the ISR and is associated with intellectual disabilities. By creating a mouse model carrying this pathogenic variant, we asked whether the mutation directly causes learning and memory deficits. In addition, this model allowed us to explore how persistent and selective ISR activation reshapes gene expression in the brain, affects different types of neurons and synaptic functions, and ultimately influences behavior. It also provides a framework for investigating strategies to reverse ISR-driven cognitive dysfunction. RESULTS: We generated Ppp1r15bR658C mice carrying the human pathogenic variant. This mutation impairs PPP1R15B's interaction with PP1, disrupting phosphatase complex activity causing persistent ISR activation (increased eIF2a phosphorylation) and reduced protein synthesis. These mice showed pronounced impairments in long-term memory and hippocampal synaptic plasticity, which were rescued by genetically inhibiting the ISR, directly linking persistent ISR activity to cognitive deficits. Ribosome profiling revealed broad changes in gene expression and mRNA translation, including increased production of ISR effectors such as ATF4 in the brain of Ppp1r15bR658C mice. However, persistent ISR activation did not trigger the usual negative feedback regulator, PPP1R15A, which could explain why the ISR remained persistently activated in the brains of Ppp1r15bR658C mice. Our study of a disease-associated PPP1R15B variant led us to examine its evolutionarily related, highly optimized viral counterpart DP71L, a small protein encoded by African Swine Fever virus. DP71L is composed solely of PP1- and eIF2-binding motifs, and represents the smallest member of the phosphatase cofactor family capable of inhibiting the ISR. Mutational, structural, and functional analyses revealed molecular insights into the mechanism by which DP71L operates as a potent pan-ISR inhibitor. Notably, treatment with DP71L reversed cognitive and synaptic deficits in mouse models of Down syndrome, Alzheimer's disease, and aging, all conditions characterized by persistent ISR activation. Finally, we also showed that DP71L was sufficient to enhance long-term memory and synaptic plasticity in healthy mice, highlighting its therapeutic potential. CONCLUSION: Persistent ISR activation across multiple neurological disorders drives cognitive and synaptic impairments by reprogramming brain cells into a maladaptive state. The evolutionarily engineered pan‑ISR inhibitor DP71L resets the ISR and reverses these deficits, even enhancing long‑term memory in healthy mice. Persistent activation of the integrated stress response (ISR) drives cognitive decline across multiple models of neurological dysfunction.: We generated a genetic mouse model carrying a human pathogenic PPP1R15B variant linked to intellectual disability, which disrupts the PPP1R15B•PP1 phosphatase complex, impairs protein synthesis, and causes deficits in synaptic plasticity and long-term memory. By leveraging insights from the African Swine Fever Virus, we characterized DP71L, a viral orthologue of PPP1R15B that acts as a highly efficient phosphatase-cofactor mimic. DP71L potently suppresses the ISR and restores long-term memory in mouse models of Alzheimer's disease, Down syndrome, aging, and even enhances long-term memory in healthy mice. [ABSTRACT FROM AUTHOR]