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.

1Altos Labs, Inc., Bay Area Institute, Redwood City, California, 94665, USA · biorxiv

Paper

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, Alzheimer 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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Research summary

The paper claims that the viral orthologue DP71L can inhibit chronic ISR activation, thereby improving cognitive function and synaptic plasticity in models of cognitive decline. This research is relevant as it explores mechanisms that could potentially address cognitive dysfunction associated with aging and age-related diseases, suggesting a pathway to mitigate cognitive decline rather than merely treating symptoms.

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