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Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

ABSTRACT: The integrated stress response (ISR) is essential for cellular homeostasis and cognitive function. Here, we investigated how persistent ISR activation impacts cognitive performance by studying the PPP1R15BR658C genetic variant associated with intellectual disability. To model this condition, we generated a knock-in mouse line carrying the pathogenic allele. We found that this variant destabilizes the PPP1R15B•PP1 phosphatase complex, causing persistent ISR activation, impaired protein synthesis, and long-term memory deficits. Importantly, we demonstrated that the cognitive and synaptic impairments in Ppp1r15bR658C mice arise directly from ISR activation. Furthermore, we characterized DP71L, a viral orthologue of PPP1R15B, revealing new molecular and structural insights as a potent pan-ISR inhibitor. Remarkably, DP71L reversed the cognitive and synaptic deficits across diverse conditions—including Down syndrome, Alzheimer’s disease and aging—and enhanced synaptic plasticity and memory in healthy mice. Our findings illustrate how human genetics and viral adaptations converge to unlock potential innovative therapeutic strategies for cognitive disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE310398 | GEO | 2026/04/09

REPOSITORIES: GEO

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ISR activation mediates the behavioral and neurophysiological abnormalities in Down syndrome

Project description:Down syndrome (DS) is the most common genetic cause of intellectual disability and a major biomedical concern. Despite a general consensus that protein homeostasis is essential for normal brain function, little is known about its role in DS. Here, we show that the integrated stress response (ISR)—a conserved signaling network that maintains proteostasis by controlling protein synthesis—is activated in the brains of DS mice and individuals with DS, leading to reduced translation. Genetic and pharmacological suppression of the ISR, either by inhibiting the ISR-initiating double-stranded RNA-activated protein kinase (PKR) or boosting the function of the eIF2•eIF2B complex, which becomes limiting upon ISR activation, de-repressed translation, reversed enhanced inhibitory synaptic transmission, and rescued the deficits in synaptic plasticity and memory in DS mice. Our findings unveil a crucial role for the ISR in DS pathophysiology and suggest tuning of the ISR as a promising therapeutic intervention for DS.

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