Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics

Torkenczy, K.; Reineke, L. C.; Dooling, S. W.; Henderson, B. W.; Itzhak, D.; Yang, B.; He, D.; Myers, R. M.; Walter, P.; Tyanova, S.; Costa-Mattioli, M.

doi:10.1101/2025.02.28.640905

bioRxiv · 10.1101/2025.02.28.640905

Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics

Torkenczy, K.·Reineke, L. C.·Dooling, S. W.·Henderson, B. W.·Itzhak, D.·Yang, B.·He, D.·Myers, R. M.·Walter, P.·Tyanova, S.·Costa-Mattioli, M.

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Abstract

Persistent activation of the integrated stress response (ISR) is a major driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. Using a new mouse model (Ppp1r15bR658C mice) that mimics the persistent ISR activation and cognitive decline observed in humans, we generated the first single-cell ISR atlas of the brain. By integrating single-cell RNA-seq and single-cell ATAC-seq with proteomics, we discovered that distinct brain cell types respond differently to persistent ISR activation and elicit cell-type-specific ISR programs. Interestingly, chromatin accessibility analyses revealed that the ISR downstream factor ATF4 is a key ISR effector in GABAergic neurons, while AP-1 (JUNB) is implicated in glutamatergic neurons. More importantly, selective deletion of ATF4 in GABAergic neurons--but not in glutamatergic neurons--impacts ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on unique ISR downstream effectors to regulate mnemonic processes. Furthermore, we defined a comprehensive molecular signature of persistent ISR activation, which we showed could serve as a biomarker for cognitive dysfunction across neurodevelopmental, neurodegenerative disorders and normal aging. This multi-omic framework provides a key platform for exploring and validating new scientific hypotheses, significantly advancing our understanding of ISR-related brain disorders.

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Torkenczy, K., Reineke, L. C., Dooling, S. W., Henderson, B. W., Itzhak, D., Yang, B., He, D., Myers, R. M., Walter, P., Tyanova, S., Costa-Mattioli, M.. 2025-03-02. Mapping the ISR Landscape in Cognitive Disorders via single-cell multi-omics. https://doi.org/10.1101/2025.02.28.640905

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