Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction

Reineke, L. C.; Zhu, P. J.; Dalwadi, U.; Dooling, S. W.; Liu, Y.; Wang, I.-C.; Young-Baird, S.; Okoh, J.; Kuncha, S. K.; Zhou, H.; Kannan, A.; Park, H.; Debeaubien, N. A.; Croll, T.; Lee, D. J.; Arthur, C.; Dever, T. E.; Walter, P.; Chen, J.; Frost, A.; Costa-Mattioli, M.

doi:10.1101/2025.02.28.640897

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bioRxiv · 10.1101/2025.02.28.640897

Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction

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Abstract

The integrated stress response (ISR) is a highly conserved network essential for maintaining cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance, primarily focusing on a PPP1R15BR658C genetic variant associated with intellectual disability. By generating a novel mouse model that mimics this human condition, we revealed that this variant destabilizes the PPP1R15B*PP1 phosphatase complex, resulting in chronic ISR activation, impaired protein synthesis, and deficits in long-term memory. Importantly, we found that the cognitive and synaptic deficits in Ppp1r15bR658C mice are directly due to ISR activation. Leveraging insights from evolutionary biology, we characterized DP71L, a viral orthologue of PPP1R15B, through detailed molecular and structural analyses, uncovering its mechanism of action as a potent pan-ISR inhibitor. Remarkably, we found that DP71L not only buffers cognitive decline associated with a wide array of conditions--including Down syndrome, Alzheimers disease and aging--but also enhances long-term synaptic plasticity and memory in healthy mice. These findings highlight the promise of utilizing evolutionary insight to inform innovative therapeutic strategies.

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Reineke, L. C., Zhu, P. J., Dalwadi, U., Dooling, S. W., Liu, Y., Wang, I.-C., Young-Baird, S., Okoh, J., Kuncha, S. K., Zhou, H., Kannan, A., Park, H., Debeaubien, N. A., Croll, T., Lee, D. J., Arthur, C., Dever, T. E., Walter, P., Chen, J., Frost, A., Costa-Mattioli, M.. 2025-03-02. Harnessing the Evolution of Proteostasis Networks to Reverse Cognitive Dysfunction. https://doi.org/10.1101/2025.02.28.640897

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