Adhesion G protein-coupled receptor ADGRG1 promotes protective microglial response in Alzheimer’s disease
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ABSTRACT:
PROVIDER: PRJNA1142856 | ENA |
REPOSITORIES: ENA
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Project description:Microglia play critical roles in maintaining brain development, homeostasis, and response to aging and diseases like Alzheimer's disease (AD). Genetic studies highlight microglia's role in AD susceptibility, but the mechanisms mediating protective responses remain largely unknown. Gpr56/Adgrg1, is one of the few genes specifically expressed in yolk-sac-derived microglia, as compared with other mononuclear phagocytes. This study reveals its role in AD pathology, particularly in modulating microglial protective responses to amyloid deposition. Utilizing constitutive and inducible microglial Adgrg1 knockouts in the 5xFAD mouse model, we demonstrate that Adgrg1 deficiency leads to increased amyloid deposition, exacerbated neuropathology, and accelerated cognitive impairment. Transcriptomic analyses reveal a distinct microglial state characterized by downregulated genes associated with homeostasis, phagocytosis, and lysosomal functions. Functional assays in mouse models and human iPSC-derived microglia support the requirement for microglial ADGRG1 in efficient Aβ phagocytosis. Collectively, these results uncover a GPCR-dependent mechanism that instructs beneficial microglial functions in response to Aβ, pointing towards potential therapeutic strategies designed to alleviate disease progression by enhancing microglial functional competence.
2025-07-25 | GSE273690 | GEO
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor GPR56/ADGRG1 inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of parental- versus GPR56 knockout-GICs to identify gene expression changes upon GPR56 knockout
2017-10-31 | GSE104653 | GEO
Project description:A mesenchymal transition occurs both during natural evolution of glioblastoma (GBM) and in response to therapy. However, the molecular mechanisms underlying mesenchymal differentiation are not well understood. We have found that the adhesion G protein-coupled receptor, GPR56/ADGRG1, inhibits mesenchymal differentiation and radioresistance in glioblastoma stem-like initiating cells (GICs). Here, we have performed microarray analysis of control- versus GPR56 knockdown-GICs to characterize gene expression changes upon GPR56 knockdown and identify a gene expression signature associated to GPR56.
2017-10-01 | GSE94765 | GEO
Project description:The placenta, forming the maternal–fetal interface, is essential for the survival and development of the fetus. It has been shown that the basic helix-loop-helix (bHLH) transcription factor Hand1 plays an important role in trophoblast giant cells (TGCs) differentiation during placental development in mice. However, the underlying molecular mechanism remains elusive. We hereby report that Adgrg1 (GPR56), a G protein coupled receptor, was a new transcriptional target of Hand1. Hand1 activated the expression of Adgrg1 by binding to its promoter region during TGCs differentiation. Double in situ hybridization revealed co-expression of Hand1 and Adgrg1 in TGCs, and Adgrg1 was located to Prl2c2+ TGCs in the junctional zone of the placenta. Knockdown of Adgrg1 not only led to increased expression of Prl2c2, but also the improvement of cell migration during TGC differentiation. Moreover, the ligands of Adgrg1, Tgm2 and Col3a1, were expressed in Prl2c2+ TGCs located in the placental junctional zone and maternal spiral arteries, respectively, further providing preconditions for the function of Adgrg1 in TGCs. Collectively, these results demonstrate that Adgrg1 is a new transcriptional target of Hand1, affecting Prl2c2 expression and cell migration during TGCs differentiation. Tgm2 and Col3a1 may be involved in TGC differentiation regulated by Adgrg1 in the manners of autocrine or paracrine. As a transmembrane receptor, Adgrg1 perhaps could act as a potential therapeutic target for placental-associated diseases caused by abnormal trophoblast migration, providing new insights for the preventions and therapies of placenta-related diseases.
2022-01-12 | GSE193214 | GEO
Project description:ADGRG1/GPR56 was knocked down by two different shRNAs in cord blood CD34+ cells via lentiviral transduction. GFP was used as marker indicating successful transduction.
2022-02-06 | GSE150175 | GEO
Project description:We founed enhanced Gpr56/Adgrg1 mRNA expression in bone tropic mouse breast cancer cell lines, 4T1.3, grown in a bone cavity, compared with in vitro culture condition. Thus, we examined about the function of Gpr56/Adgrg1 in tumor growth of vitro culture condition with its ligand, type III collagen.
2022-08-01 | GSE154908 | GEO
Project description:G protein-coupled receptor 56 (GPR56/ADGRG1) is an adhesion GPCR with an essential role in brain development and cancer. Elevated expression of GPR56 was observed in the clinical specimens of Glioblastoma (GBM), a highly invasive primary brain tumor. However, we found the expression to be variable across the specimens, presumably due to the intratumor heterogeneity of GBM. Therefore, we re-examined GPR56 expression in public domain spatial gene expression data and single-cell expression data for GBM, which revealed that GPR56 expression was high in cellular tumors, infiltrating tumor cells, and proliferating cells, low in microvascular proliferation and peri-necrotic areas of the tumor, especially in hypoxic mesenchymal-like cells. To gain a better understanding of the consequences of GPR56 downregulation in tumor cells and other molecular changes associated with it, we generated a sh-RNA-mediated control and GPR56 knockdown in the GBM cell line U373 and performed transcriptomics, proteomics, and phospho-proteomics analysis and using the data we propose a putative model to explain this functional and regulatory relationship of the two proteins.
2022-05-04 | PXD031569 | Pride
Project description:GPR56 is a widely expressed adhesion GPCR (AGPCR) that has pleotropic roles in brain development, platelet function, cancer, and more. Nearly all AGPCRs possess extracellular regions that bind protein ligands and conceal a cryptic tethered peptide agonist. AGPCR reception of mechanical or shear force is thought to release the tethered agonist permitting its binding to the AGPCR orthosteric site for consequent activation of G protein signaling. This multistep mechanism of AGPCR activation is difficult to target, emphasizing the need for tool compounds and potential therapeutics that modulate AGPCRs directly. We expanded our cell-based pilot screen for GPR56 small molecule activators to screen >200,000 compounds and identified two promising agonists: 2-(furan-2-yl)-1-[(4-phenylphenyl)carbonyl]pyrrolidine, or compound 4, and propan-2-yl-4-(2-bromophenyl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carboxylate, or compound 36. Both compounds activated GPR56 receptors enginered to have impaired tethered agonists and/or be cleavage deficient. Compound 4 activated a subset of group VIII AGPCRs while compound 36 had exclusive specificity for GPR56 among the GPCRs tested. Compound 36 SAR analysis identified an analog with the isopropyl R group replaced with a cyclopentyl ring and the electrophilic bromine replaced with a CF3 group. Analog 36.40 had 40% increased potency over compound 36 and was 20-fold more potent than synthetic peptidomimetics designed from the GPR56 tethered agonist. The new GPCR56 tool compounds discovered in this screen may be used to further advance understanding of GPR56 function and aid development of AGPCR-targeted therapeutics. SIGNIFICANCE STATEMENT: Adhesion G protein coupled receptors (AGPCRs) are a large, clinically relevant class of GPCRs with no available therapeutics, in part due to their unique mechanism of activation. GPR56 is a widely expressed model AGPCR involved in cancer metastasis, hemostasis, and neuron myelination. In the present study, we identified novel small molecule agonists for GPR56. These molecules are among the most potent identified thus far and may become useful leads in the development of a GPR56-targeted therapeutic.
| S-EPMC10289240 | biostudies-literature
Project description:Alzheimer’s disease is associated with disrupted circadian rhythms and clock gene expression. REV-ERBα (Nr1d1) is a circadian transcriptional repressor involved in the regulation of lipid metabolism and macrophage function. While global REV-ERBα deletion increases microglial activation and mitigates amyloid plaque formation, the cell-autonomous effects of microglial REV-ERBα deletion in healthy brain and in tauopathy are unexplored. Here, we show that microglial REV-ERBα deficient enhances inflammatory signaling, disrupts lipid metabolism, and causes lipid droplet (LD) accumulation specifically in male microglia. Inflammation and LD accumulation combine to inhibit microglial tau phagocytosis, which can be partially rescued by blockage of lipid droplet formation. Microglial REV-ERBα deletion exacerbates tau aggregation and neuroinflammation in P301S and AAV-P301L tauopathy models in male, but not female mice. These data demonstrate the importance of microglial lipid droplets in tau accumulation and reveal REV-ERBα as a therapeutically accessible, sex-dependent regulator of microglial inflammatory signaling, lipid metabolism, and tauopathy.
2023-08-09 | PXD043877 | Pride
Project description:a. Human microglia play a pivotal role in neurological diseases, but few targeted therapies that directly modulate microglial state or function exist due to an incomplete understanding of microglial heterogeneity. We use single-cell RNA sequencing to profile live human microglia from autopsies or surgical resections across diverse neurological diseases and central nervous system regions. We observe a central divide between oxidative and heterocyclic metabolism and identify subsets associated with antigen presentation, motility, and proliferation. Specific subsets are enriched in susceptibility genes for neurodegenerative diseases or the disease-associated microglial signature. We validate subtypes in situ with an RNAscope-immunofluorescence pipeline and leverage our dataset as a classification resource, finding that iPSC model systems recapitulate substantial in vivo heterogeneity. Finally, we identify and validate candidates for chemically inducing subtype-specific states in vitro, showing that Camptothecin downregulates the transcriptional signature of disease-enriched subsets and upregulates a signature previously shown to be depleted in Alzheimer’s.
2025-05-19 | PXD033844 | Pride