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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE226385 | GEO | 2023/04/26

REPOSITORIES: GEO

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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 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: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

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

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

| PRJNA940101 | 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 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 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 I

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

| PRJNA940104 | ENA

Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway.

Project description:The presence of DNA in the cytoplasm of mammalian cells is a danger signal that triggers host immune responses such as the production of type I interferons. Cytosolic DNA induces interferons through the production of cyclic guanosine monophosphate-adenosine monophosphate (cyclic GMP-AMP, or cGAMP), which binds to and activates the adaptor protein STING. Through biochemical fractionation and quantitative mass spectrometry, we identified a cGAMP synthase (cGAS), which belongs to the nucleotidyltransferase family. Overexpression of cGAS activated the transcription factor IRF3 and induced interferon-? in a STING-dependent manner. Knockdown of cGAS inhibited IRF3 activation and interferon-? induction by DNA transfection or DNA virus infection. cGAS bound to DNA in the cytoplasm and catalyzed cGAMP synthesis. These results indicate that cGAS is a cytosolic DNA sensor that induces interferons by producing the second messenger cGAMP.

| S-EPMC3863629 | biostudies-literature

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