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Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience

ABSTRACT: Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience

PROVIDER: PRJNA940101 | ENA |

REPOSITORIES: ENA

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Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

Project description:Here we report that activation of cyclic GMP-AMP synthase (cGAS) diminishes cognitive resilience by decreasing the neuronal transcriptional network of myocyte enhancer factor 2c (MEF2C) through type I interferon (IFN-I) signaling. Pathogenic tau activates cGAS and IFN-I responses in microglia, in part mediated by cytosolic leakage of mitochondrial DNA. Genetic ablation of cGAS in tauopathy mice diminished microglial IFN-I response, preserved synapse integrity and plasticity, and protected against cognitive impairment without affecting the pathogenic tau load. cGAS ablation enhanced, while activation of IFN-I downregulated, neuronal MEF2C expression network linked with cognitive resilience in AD.

2023-04-26 | GSE226381 | GEO

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience I

Project description:Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience I

| PRJNA940104 | ENA

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience IV

Project description:Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience IV

| PRJNA940106 | ENA

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

Project description:Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience II

| PRJNA940108 | ENA

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience III

Project description:Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience III

| PRJNA940107 | ENA

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience IV

Project description:Pharmacological inhibition of cGAS with TDI-6570 protected against the synaptic loss and cognitive deficits in P301S tauopathy model, likely via enhancing MEF2C transcriptional network and associated cognitive resilience

2023-04-26 | GSE226383 | GEO

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience III

Project description:To induce chronic IFN-I activation, we injected wildtype and Ifnar1–/– mice with five treatments of DMXAA, a STING agonist, followed by snRNA-seq analysis of hippocampal tissues. In wildtype mice, we showed that microglia had the strongest IFN response to STING activation of all cell types. Ablation of interferon alpha and beta receptor 1 (IFNAR1) abolished microglial IFN-I response and suppression of neuronal MEF2C transcriptional network

2023-04-26 | GSE226382 | GEO

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-04-26 | GSE226385 | GEO

Cyclic GMP-AMP synthase and interferon activation diminish MEF2C-mediated cognitive resilience I

Project description:Analysis of differentially expressed genes (DEGs) revealed a striking upregulation of interferon genes in P301S, compared to non-transgenic hippocampi, and enrichment of transcription factor motifs of interferon-response factors (IRFs) and interferon-sensitive response elements (ISREs). Cgas deletion reduced the induction of a subset of tau-stimulated inflammatory and cytokine expression including interferon stimulated genes such as Stat1, Ddx60, Isg20, Rnf213, Parp12, Ifi35, and Sp100. Thus, microglial cGAS promotes IFN-I expression in response to tau.

2023-04-26 | GSE226380 | GEO

Dysfunctional telomeres trigger cellular senescence mediated by cyclic GMP-AMP synthase.

Project description:Defective DNA damage response (DDR) signaling is a common mechanism that initiates and maintains the cellular senescence phenotype. Dysfunctional telomeres activate DDR signaling, genomic instability, and cellular senescence, but the links among these events remains unclear. Here, using an array of biochemical and imaging techniques, including a highly regulatable CRISPR/Cas9 strategy to induce DNA double strand breaks specifically in the telomeres, ChIP, telomere immunofluorescence, fluorescence in situ hybridization (FISH), micronuclei imaging, and the telomere shortest length assay (TeSLA), we show that chromosome mis-segregation due to imperfect DDR signaling in response to dysfunctional telomeres creates a preponderance of chromatin fragments in the cytosol, which leads to a premature senescence phenotype. We found that this phenomenon is caused not by telomere shortening, but by cyclic GMP-AMP synthase (cGAS) recognizing cytosolic chromatin fragments and then activating the stimulator of interferon genes (STING) cytosolic DNA-sensing pathway and downstream interferon signaling. Significantly, genetic and pharmacological manipulation of cGAS not only attenuated immune signaling, but also prevented premature cellular senescence in response to dysfunctional telomeres. The findings of our study uncover a cellular intrinsic mechanism involving the cGAS-mediated cytosolic self-DNA-sensing pathway that initiates premature senescence independently of telomere shortening.

| S-EPMC7415994 | biostudies-literature

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