Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation.
Overview
- Altos Labs, Inc., Bay Area Institute, Redwood City, CA 94665
- HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806
- Department of Neuroscience, Baylor College of Medicine, Houston, TX 77030
Abstract
Persistent activation of the integrated stress response (ISR) is a central driver of cognitive decline in both neurodevelopmental and neurodegenerative disorders. However, the cell type–specific mechanisms underlying these deficits remain poorly understood. By integrating single-cell RNA-seq and single-cell assay for transposase-accessible chromatin sequencing, we generated a brain ISR atlas using Ppp1r15bR658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. We find that distinct brain cell types differentially engage transcriptional and chromatin remodeling programs. Notably, selective deletion of the major ISR downstream effector ATF4 in GABAergic neurons, but not in glutamatergic neurons, exacerbates ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes rely on distinct ISR effectors. We define a molecular single-cell signature of persistent ISR activation that serves as a metric of ISR-mediated cellular vulnerability and as a biomarker for cognitive dysfunction across human cognitive disorders. These findings demonstrate that cell type–specific responses drive cognitive dysfunction during persistent ISR activation.
Reproduced under the paper's license (CC BY), from the paper cited above.
Code
The paper links to its data, not to its authors' code: see the Data section.
The paper's code and data availability statement is in the Data section.
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Data
Datasets cited
- geo:GSE314068 — at NCBI GEO; found in “Data, Materials, and Software Availability”
Data, Materials, and Software Availability
The scRNA-seq and scATAC-seq data were deposited in the Gene Expression Omnibus (GEO) database repository (GSE314068 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 10 authors, 4 keywords, 11 MeSH terms, 2 funders, 145 references, 1 integrity notice.
Cite
This paper
Torkenczy, K., Reineke, L. C., Dooling, S. W., Henderson, B. W., Yang, B., He, D., Myers, R. M., Walter, P., Tyanova, S., & Costa-Mattioli, M. (2026). Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation. Proceedings of the National Academy of Sciences of the United States of America, 123(29), e2537017123. https://
BibTeX
@article{torkenczy2026di
author = {Torkenczy, Kristof and Reineke, Lucas C and Dooling, Sean W and Henderson, Benjamin W and Yang, Benjamin and He, Dongze and Myers, Richard M and Walter, Peter and Tyanova, Stefka and Costa-Mattioli, Mauro},
title = {{Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation}},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = jul,
volume = {123},
number = {29},
pages = {e2537017123},
publisher = {National Academy of Sciences},
issn = {0027-8424},
doi = {10.1073/
url = {https://
pmid = {42446983},
pmcid = {PMC13389509}
}
RIS
TY - JOUR
AU - Torkenczy, Kristof
AU - Reineke, Lucas C
AU - Dooling, Sean W
AU - Henderson, Benjamin W
AU - Yang, Benjamin
AU - He, Dongze
AU - Myers, Richard M
AU - Walter, Peter
AU - Tyanova, Stefka
AU - Costa-Mattioli, Mauro
TI - Distinct cell type-specific mechanisms underlie cognitive dysfunction during persistent integrated stress response activation
T2 - Proceedings of the National Academy of Sciences of the United States of America
J2 - Proc Natl Acad Sci U S A
PY - 2026
DA - 2026/
VL - 123
IS - 29
SP - e2537017123
SN - 0027-8424
PB - National Academy of Sciences
DO - 10.1073/
UR - https://
LA - en
ER -
CSL-JSON
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"author": [
{
"family": "Torkenczy",
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