Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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. Here, by integrating single-cell RNA-seq and single-cell ATAC-seq, we generated an ISR atlas of the brain using Ppp1r15bR658C mice, a clinically relevant model of intellectual disability characterized by selective and persistent ISR activation. Unexpectedly, our analysis revealed 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—impacts ISR-mediated cognitive decline in Ppp1r15bR658C mice, demonstrating that different neuronal subtypes have different dependencies for ISR effectors. Finally, we defined 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 cogntive disorders. These findings dissect the cell-type-specific architecture of the ISR in the brain, providing new insights into the biological mechanisms driving ISR-dependent cognitive decline.

ORGANISM(S): Mus musculus

PROVIDER: GSE314068 | GEO | 2026/07/01

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

Project description: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.

2026-04-09 | GSE310398 | GEO

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

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

| PRJNA1389920 | ENA

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.

2019-11-02 | GSE138371 | GEO

SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1beta

Project description:Aging is the predominant risk factor for neurodegenerative diseases. One key phenotype as brain ages is the aberrant innate immune response characterized by proinflammation. However, the molecular mechanisms underlying aging-associated proinflammation are poorly defined. Whether chronic inflammation plays a causal role in cognitive decline in aging and neurodegeneration has not been established. Here we established a mechanistic link between chronic inflammation and aging microglia, and demonstrated a causal role of aging microglia in neurodegenerative cognitive deficits. Expression of microglial SIRT1 reduces with the aging of microglia. Genetic reduction of microglial SIRT1 elevates IL-1Î² selectively, and exacerbates cognitive deficits in aging and in transgenic mouse models of frontotemporal dementia (FTD). Interestingly, the selective activation of IL-1Î² transcription by SIRT1 deficiency is likely mediated through hypomethylating the proximal promoter of IL-1Î². Consistent with our findings in mice, selective hypomethylation of IL-1Î² at two CpG sites are found in normal aging humans and demented patients with tauopathy. Our findings reveal a novel epigenetic mechanism in aging microglia that contributes to cognitive deficits in neurodegenerative diseases. Study of changes related to alterations of SIRT1 levels in microglia of young and aged animals and in models of neurodegenerative dementia

2014-10-01 | E-GEOD-56452 | biostudies-arrayexpress

ISR pathway activation signatures in MEFs: GCN2 and PERK

Project description:In response to different cellular stressors, the ISR kinases, PERK, PKR, HRI and GCN2, activate downstream transcriptional programs. While the core ISR transcription program is well characterized, markers that are specific to each individual ISR kinase activation pathway are not known. To identify markers that are induced by PERK or GCN2, but not the other ISR kinases, we subjected WT, GCN2-/-, and PERK-/- MEFs to amino acid starvation (RPMI 1640 SILAC -Lys -Arg) or Thapsigargin (200nM) treatment for 6 hours to activate the GCN2 and PERK pathways, respectively and performed RNA sequencing.

2022-07-01 | GSE179559 | GEO

RNA-seq of endothelial cells, astrocytes and microglia in wild-type and endothelial cell-specific Nrf2 knockout mice, in a model of systemic inflammation

Project description:Systemic inflammation can lead to neuro-inflammation with both acute consequences and long-lasting deleterious effects, such as cognitive decline and the exacerbation of neurodegenerative disease progression. We investigated the role in regulating this process of the activation of the transcription factor Nrf2 in brain endothelial cells.

2024-09-03 | E-MTAB-14404 | biostudies-arrayexpress

Activation of ISR/ATF4 signaling depletes HIV reservoir in CD4+ T cells

Project description:Latent HIV reservoirs are extremely stable which pose a tremendous challenge to eradicate HIV. Here, we show that HIV explores the integrated stress response (ISR) signaling to establish its quiescent infection, refractory to the clearance for its persistence. HA15, a recently characterized specific ISR agonist, activates ATF4/CHOP signaling to not only disrupt HIV latency but also reduce HIV+ cells in the primary CD4+ T cell model of HIV latency without the induction of cell death in the HIV negative primary CD4+ T cells and the impact of viability in resting CD4+ T cells isolated from people living with HIV (PLWH). Mechanistically, the reduction of HIV+ cells by ISR/ATF4 activation is associated with the enhancement of cellular apoptosis. However, this mainly occurs in the HIV translation negative CD4+ T cells. In fact, ISR/ATF4 activation-induced cell death largely occurs in HIV transcription active (HIV gag-pol) CD4+ T cells. This is involved in HIV RNA-induced innate immune IFIT signaling. During the acute SIV infection in the rhesus macaques, the induction of ATF4 is associated with decrease of SIV reservoir in the intestine in vivo. When further tested in the resting CD4+ T cells isolated from PLWH on ART, the induction of ISR/ATF4 signaling by HA15 reduced HIV DNA reservoir. These findings support that inactivation of ISR/ATF4 signaling is associated with the maintenance of the stable and quiescent HIV reservoirs while enforced ISR/ATF4 signaling reduces translation quiescent HIV reservoirs in CD4+ T cells.

2022-12-05 | GSE210824 | GEO

Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

Project description:Harnessing Viral Strategies to modulate the ISR and Reverse Cognitive Dysfunction

| PRJNA1365879 | ENA

Multiomic analysis identifies involvement of complement-dependent pathways in outcomes after repetitive mild closed head injury

Project description:Repetitive mild closed head injury (rmCHI) is a common type of traumatic brain injury and its incidence is increasing, not least due to an increase in the number of sports-related injuries. The underlying neuroimmune mechanisms secondary to trauma that link rmCHI to cognitive decline are not well understood, and the role of complement in this context is largely unexplored. We developed a mouse model of rmCHI and demonstrated complement activation in the brain and cognitive decline, measured 21 days after cessation of injury. These outcomes were accompanied by alterations in local and peripheral immune cell recruitment, together with changes in microglial activation status, as determined by mass cytometry and microscopy. RNAseq and proteomic analysis further revealed major changes in neurodegenerative associated pathways after rmCHI, such as pathways involved neuron development, wound healing and neuronal apoptosis. Complement inhibition initiated after cessation of injury modulated rmCHI-induced changes and protected against cognitive decline.

2025-12-01 | PXD053772 | Pride

ISR pathway activation signatures in MEFs: GCN2 and PERK

Project description:ISR pathway activation signatures in MEFs: GCN2 and PERK

| PRJNA744201 | ENA