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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE226381 | 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

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2023-04-26 | GSE226382 | GEO

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

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Neuronal identity defines a-synuclein and tau toxicity

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2023-03-21 | GSE223626 | GEO

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Project description:The dynamic function of synapses is critical for encoding memories in the brain. Pathogenic tau obstructs glutamatergic synapse function by blocking long-term potentiation (LTP), representing a key mechanism underlying memory impairment in Alzheimer s disease (AD). Here we developed a strategy for KIdney/BRAin (KIBRA)-mediated LTP repair in neurons with pathogenic tau using the C-terminus of KIBRA (CT-KIBRA). We show that CT-KIBRA restores LTP and memory in transgenic mice expressing human tau that mimics pathogenic hyperacetylated tau found in AD and other tauopathies. CT-KIBRA did not alter tau levels or prevent tau-induced synapse loss in the transgenic mouse brain, instead, we show that CT-KIBRA binds to and stabilizes protein kinase M zeta (PKM zeta) to maintain plasticity and memory despite tau pathogenesis. Further, in humans we established that KIBRA levels in brain and cerebrospinal fluid correlate with tau and cognitive impairment in tauopathies. Our study provides evidence to support KIBRA as a tauopathy-related synaptic biomarker and a synapse repair therapeutic to ameliorate cognitive impairment.

2022-10-11 | MSV000090510 | MassIVE

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2022-04-26 | GSE201084 | GEO

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2021-02-02 | PXD023562 | Pride

ARF1 prevents aberrant type I IFN induction by regulating STING activation and recycling

Project description:Type I interferon (IFN) signalling is tightly controlled. Upon recognition of DNA by cyclic GMP-AMP synthase (cGAS), stimulator of interferon genes (STING) translocates along the endoplasmic reticulum (ER)-Golgi axis to induce IFN signalling. Afterwards, signal termination is achieved through autophagic degradation of STING, or STING recycling by retrograde COPI-mediated transport. Here we identify the GTPase ARF1 as a negative regulator of cGAS-STING signaling. Heterozygous ARF1 missense mutations cause a novel type I interferonopathy associated with enhanced IFN stimulated gene production. Expression of patient-derived, GTPase-defective, ARF1 in cell lines and primary cells results in increased cGAS-STING dependent type I IFN signalling. Mechanistically, mutated ARF1 both induces activation of cGAS by aberrant mitochondrial DNA, and promotes accumulation of active STING at the Golgi/ERGIC due to defective COPI retrograde transport. Our data establish ARF1 as a key factor in cGAS-STING homeostasis, which is required to maintain mitochondrial integrity and promote STING recycling.

2022-06-23 | MSV000089711 | MassIVE

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Project description:Most systemic lupus erythematosus (SLE) patients are photosensitive and ultraviolet B light (UVB) exposure worsens cutaneous disease and precipitates systemic flares of disease. The pathogenic link between skin disease and systemic exacerbations in SLE remains elusive. In an acute model of UVB-triggered inflammation, we observed that a single UV exposure triggered a striking IFN-I signature not only in the skin, but also in the blood and kidneys. The early IFN-I signature was significantly higher in female compared to male mice. The early IFN-I response in the skin was almost entirely, and in the blood partly, dependent on the presence of cGAS, as was skin inflammatory cell infiltration. Inhibition of cGAMP hydrolysis augmented the UVB-triggered IFN-I response. UVB skin exposure leads to cGAS-activation and both local and systemic IFN-I signature and could contribute to acute flares of disease in susceptible subjects such as patients with SLE.

2020-04-13 | GSE148535 | GEO

Transcriptomic evaluation of tau and TDP-43 synergism shows tauopathy predominates.

Project description:Cellular responses to co-morbid tau and TDP-43 preceding neurodegeneration have not been characterized. In this study, we evaluate transcriptomic changes at time-points preceding frank neuronal loss using a C. elegans model of tau and TDP-43 co-expression. We find significant differential expression and exon usage in genes enriched in multiple pathways including lipid metabolism and lysosomal degradation. We note that tau related changes largely resemble tau/TDP-43 changes. We test loss-of-function mutations in a subset of tau and TDP-43 responsive genes, identifying new modifiers of neurotoxicity. Characterizing early cellular responses to tau and TDP-43 co-pathology is critical for understanding protective and pathogenic responses to mixed proteinopathies, and an important step in developing therapeutic strategies protecting against pathological tau and TDP-43 in AD.

2024-03-15 | GSE249339 | GEO

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