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

Lucas C. Reineke; Ping Jun Zhu; Udit Dalwadi; Sean W. Dooling; Yuwei Liu; I. Ching Wang; Sara Young-Baird; James Okoh; Santosh Kumar Kuncha; Hongyi Zhou; Akshara Kannan; Hyekyung Park; Nicolas A. Debeaubien; Tristan Croll; D. John Lee; Christopher Arthur; Thomas E. Dever; Peter Walter; Jin Chen; Adam Frost; Mauro Costa-Mattioli

doi:10.1126/science.aea8782

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

Lucas C. Reineke, Ping Jun Zhu, Udit Dalwadi, Sean W. Dooling, Yuwei Liu, I. Ching Wang, Sara Young-Baird, James Okoh, Santosh Kumar Kuncha, Hongyi Zhou, Akshara Kannan, Hyekyung Park, Nicolas A. Debeaubien, Tristan Croll, D. John Lee, Christopher Arthur, Thomas E. Dever, Peter Walter, Jin Chen, Adam FrostMauro Costa-Mattioli^*

^*Corresponding author for this work

Biochemistry

Research output: Contribution to journal › Article › peer-review

1 Scopus citations

Abstract

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.

Original language	English
Article number	eaea8782
Pages (from-to)	eaea8782
Journal	Science
Volume	392
Issue number	6793
DOIs	https://doi.org/10.1126/science.aea8782
State	Published - 2 Apr 2026

Keywords

Animals
Mice
Cognitive Dysfunction/genetics
Protein Phosphatase 1/genetics
Neuronal Plasticity
Disease Models, Animal
Alzheimer Disease/genetics
Down Syndrome/genetics
Stress, Physiological/genetics
Humans
Cognition
Memory, Long-Term
Aging
Male
Protein Biosynthesis

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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., ... Costa-Mattioli, M. (2026). Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response. Science, 392(6793), eaea8782. Article eaea8782. https://doi.org/10.1126/science.aea8782

@article{25a5906142fe438c9abb3e146b1bfe63,

title = "Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response",

abstract = "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.",

keywords = "Animals, Mice, Cognitive Dysfunction/genetics, Protein Phosphatase 1/genetics, Neuronal Plasticity, Disease Models, Animal, Alzheimer Disease/genetics, Down Syndrome/genetics, Stress, Physiological/genetics, Humans, Cognition, Memory, Long-Term, Aging, Male, Protein Biosynthesis",

author = "Reineke, \{Lucas C.\} and Zhu, \{Ping Jun\} and Udit Dalwadi and Dooling, \{Sean W.\} and Yuwei Liu and Wang, \{I. Ching\} and Sara Young-Baird and James Okoh and Kuncha, \{Santosh Kumar\} and Hongyi Zhou and Akshara Kannan and Hyekyung Park and Debeaubien, \{Nicolas A.\} and Tristan Croll and Lee, \{D. John\} and Christopher Arthur and Dever, \{Thomas E.\} and Peter Walter and Jin Chen and Adam Frost and Mauro Costa-Mattioli",

year = "2026",

month = apr,

day = "2",

doi = "10.1126/science.aea8782",

language = "English",

volume = "392",

pages = "eaea8782",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

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Reineke, LC, Zhu, PJ, Dalwadi, U, Dooling, SW, Liu, Y, Wang, IC, Young-Baird, S, Okoh, J, Kuncha, SK, Zhou, H, Kannan, A, Park, H, Debeaubien, NA, Croll, T, Lee, DJ, Arthur, C, Dever, TE, Walter, P, Chen, J, Frost, A & Costa-Mattioli, M 2026, 'Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response', Science, vol. 392, no. 6793, eaea8782, pp. eaea8782. https://doi.org/10.1126/science.aea8782

TY - JOUR

T1 - Harnessing viral strategies to reverse cognitive dysfunction through the integrated stress response

AU - Reineke, Lucas C.

AU - Zhu, Ping Jun

AU - Dalwadi, Udit

AU - Dooling, Sean W.

AU - Liu, Yuwei

AU - Wang, I. Ching

AU - Young-Baird, Sara

AU - Okoh, James

AU - Kuncha, Santosh Kumar

AU - Zhou, Hongyi

AU - Kannan, Akshara

AU - Park, Hyekyung

AU - Debeaubien, Nicolas A.

AU - Croll, Tristan

AU - Lee, D. John

AU - Arthur, Christopher

AU - Dever, Thomas E.

AU - Walter, Peter

AU - Chen, Jin

AU - Frost, Adam

AU - Costa-Mattioli, Mauro

PY - 2026/4/2

Y1 - 2026/4/2

N2 - 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.

AB - 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.

KW - Animals

KW - Mice

KW - Cognitive Dysfunction/genetics

KW - Protein Phosphatase 1/genetics

KW - Neuronal Plasticity

KW - Disease Models, Animal

KW - Alzheimer Disease/genetics

KW - Down Syndrome/genetics

KW - Stress, Physiological/genetics

KW - Humans

KW - Cognition

KW - Memory, Long-Term

KW - Aging

KW - Male

KW - Protein Biosynthesis

UR - http://www.scopus.com/inward/record.url?scp=105034959847&partnerID=8YFLogxK

U2 - 10.1126/science.aea8782

DO - 10.1126/science.aea8782

M3 - Article

C2 - 41926581

SN - 0036-8075

VL - 392

SP - eaea8782

JO - Science

JF - Science

IS - 6793

M1 - eaea8782

ER -

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

Abstract

Keywords

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