Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ERV-Derived RNA-DNA Hybrids Upregulate C4b to Induce Microglial Synaptic Pruning in autism [RNA]

ABSTRACT: Microglia-mediated neuroinflammation has been identified as pathogenic in autism spectrum disorders (ASD). Pathogenic factors for microglial activation remain unclear. In our study, we discovered that complement C4b is highly expressed in the prefrontal cortex (PFC) neurons with SETDB1 deficiency, a high-risk gene of ASD, or by maternal inflammation (MI). Exposure to C4b led microglia to perform excessive synaptic pruning, which in turn manifested ASD-like phenotypes. Furthermore, we observed that removing microglia could improve synaptic functions, while the complete knockout of C4b could rescue all observed autistic phenotypes. The expression of C4b was contingent upon RNA-DNA hybrids formed by the reactivation of Endogenous Retroviruses (ERVs).Interestingly, the pharmacological reversal of this retrotranscriptional process with FDA-approved HIV medications significantly reduced C4b levels and ameliorated the symptoms of ASD. Our findings illuminate the pivotal role of C4b in microglia-driven synaptic pruning linked to ASD and suggest that targeting ERV reactivation could be a promising therapeutic strategy with existing FDA-approved HIV drugs.

ORGANISM(S): Mus musculus

PROVIDER: GSE275174 | GEO | 2026/02/24

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

ERV-Derived RNA-DNA Hybrids Upregulate C4b to Induce Microglial Synaptic Pruning in autism [ChIP-seq]

Project description:Microglia-mediated neuroinflammation has been identified as pathogenic in autism spectrum disorders (ASD). Pathogenic factors for microglial activation remain unclear. In our study, we discovered that complement C4b is highly expressed in the prefrontal cortex (PFC) neurons with SETDB1 deficiency, a high-risk gene of ASD, or by maternal inflammation (MI). Exposure to C4b led microglia to perform excessive synaptic pruning, which in turn manifested ASD-like phenotypes. Furthermore, we observed that removing microglia could improve synaptic functions, while the complete knockout of C4b could rescue all observed autistic phenotypes. The expression of C4b was contingent upon RNA-DNA hybrids formed by the reactivation of Endogenous Retroviruses (ERVs). Interestingly, the pharmacological reversal of this retrotranscriptional process with FDA-approved HIV medications significantly reduced C4b levels and ameliorated the symptoms of ASD. Our findings illuminate the pivotal role of C4b in microglia-driven synaptic pruning linked to ASD and suggest that targeting ERV reactivation could be a promising therapeutic strategy with existing FDA-approved HIV drugs.

2026-02-24 | GSE275136 | GEO

Single-cell RNA sequencing reveals cellular heterogeneity of spinal microglia in neuropathic pain

Project description:Recent studies reveal that microglia modulate synaptic transmission by direct synaptic pruning. Microglia reactivation is a crucial mechanism of central sensitization in neuropathic pain, yet the exact changes of microglia during the development of neuropathic pain and its interaction with the spinal inhibitory circuits remains unclear. In this work, single-cell sequencing delineates temporal changes in spinal microglia and identifies a specific type of microglia as the subpopulation mediating synaptic pruning. We found that peripheral nerve injury induced the transition of spinal microglia from a pro-inflammatory to a “pruning” state, resulting in pain hypersensitivity by spinal disinhibition.

2024-10-24 | GSE246288 | GEO

RNA Sequencing Facilitates Quantitative Analysis of Lupus (MRL/lpr) and Control（MRL/mpj）Mouse Microglia Tanscriptomes

Project description:Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Microglia control synaptic pruning during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that microglia-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased depression- and anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. To elucidate the mechanism of synaptic pruning by microglia, we sequenced the gene expression in sorted microglia from both lupus (MRL/lpr) mice and the wild-type (MRL/mpj) controls.

2024-03-27 | GSE201282 | GEO

Moesin deficiency leads to microglia-mediated synaptic pruning and social abnormality: a post-GWAS functional genomics study

Project description:Genome-wide association studies (GWAS) implicated a noncoding antisense RNA designated as MSNP1AS in susceptibility to autism spectrum disorders (ASD). MSNP1AS binds to and downregulates the Moesin (MSN) transcript and is highly overexpressed in postmortem cerebral cortex of individuals with ASDs. However, the mechanistic link between Moesin loss in vivo and ASD-related phenotypic traits remains enigmatic. Here, we generated Moesin knockout (Msn KO) mice, on which neurobehavioral tests revealed impaired social novelty and repetitive behaviors. Single-cell transcriptomics and electrophysiology recording indicated activated status of the microglia, leading to aberrant C1q-dependent synaptic pruning followed by synaptic deficits in medial prefrontal cortex in KO mice. Aberrant regulatory pathway from sequencing data guided us to block type I interferon pathway by IFNAR1 blocking antibody via nasal administration, which rescued microglial abnormalities and social deficits in Msn KO mice. Taken together, Moesin mediates interferon signaling and synaptic pruning to affect ASD-like behaviors, providing a functional genetic link between MSN and neurobehavioral abnormalities.

2025-06-11 | GSE293405 | GEO

Drug screen combining RNA landscape analysis reveals targetable pathways in HIV-1 reactivation

Project description:We invesitgated cellular pathways required for HIV-1 activation using HIV-1-suppressing agents. Despite effective antiretroviral therapy, HIV-1-nfected cells continue to produce viral antigens and induce chronic immune exhaustion. Using a novel dual reporter system and a high-throughput drug screen, we identified FDA-approved drugs which can suppress HIV-1 reactivation in both cell line models and CD4+ T cells from virally suppressed, HIV-1-infected individuals. We identified 11 cellular pathways required for HIV-1 reactivation as druggable targets. Using differential expression analysis, gene set enrichment analysis and exon-intron landscape analysis, we examined the impact of drug treatment on the cellular environment at a genome-wide level.

2020-09-02 | GSE149353 | GEO

CaMKI dysregulation leads to autism-related phenotypes in precise synaptic connectivity, sleep, social behavior, and aging-dependent degeneration in Drosophila

Project description:Postmortem studies reveal increased density of synapses in brains of individuals with autism spectrum disorder (ASD. These observations have led to the hypothesis that defects in synaptic pruning may contribute to ASD pathology. Synaptic pruning, also called synaptic elimination or refinement, is a neuroplastic process involving the removal of ectopic synapses formed in the initial stages of neuronal development. Studies in vertebrates and invertebrates indicate that a crucial factor regulating synaptic pruning is neuronal activity, which was first hypothesized by Nobel laureates Hubel and Wiesel in the 1960s. Studies at the vertebrate retina as well as the mammalian and Drosophila neuromuscular junction (NMJ) indicate that waves of prenatal electrical activity and calcium (Ca2+) oscillations regulate the withdrawal of off-target synaptic contacts. Ca2+ oscillations regulate Ca2+-dependent molecular factors such as kinases (e.g. CaMKII), phosphatases (Calcineurin), and Ca2+-dependent adenylyl cyclases, which in turn regulate intracellular cyclic AMP (cAMP) levels for synaptic pruning in mammalian visual neurons and at the Drosophila NMJ21. Whereas a model to explain the refinement of synaptic connections often involves mechanisms based on Hebbian-like, spike-timing correlation between synaptic partners, where asynchronous inputs are removed, alternative non-Hebbian mechanisms have also been proposed that rely on activity-dependent modulation of chemorepulsion. Although some molecular aspects underlying activity-dependent synaptic refinement have recently been elucidated what molecules link dynamic levels of neuronal activity and the refinement of synaptic contacts during development remain to be elucidated. Consistent with its contributions to advance our understanding of synaptic development, Drosophila melanogaster has emerged as a suitable genetic model system for investigating fundamental mechanisms associated with ASD.

2025-10-06 | PXD061426 | Pride

RNA Sequencing Facilitates Quantitative Analysis of Wild Type(MRL-mpj) and MRL-lpr (PBS or MSC treated) Hippocampoal Transcriptomes

Project description:Up to 75% of systematic lupus erythematosus (SLE) patients experience neuropsychiatric (NP) symptoms, called neuropsychiatric SLE (NPSLE), yet the underlying mechanisms remain elusive. Complement cascades mediate synaptic pruning by microglia during early postnatal brain development. The process in NPSLE remains unclear. Here, we show that complement-coordinated elimination of synaptic terminals participated in NPSLE in MRL/lpr mice, a lupus-prone murine model. We elucidated that lupus mice developed increased anxiety-like behaviors and persistent phagocytic microglia reactivation before overt peripheral lupus pathology. Microglial engulfment of synapses explained behavioral disorders. We further determined that neuronal Nr4a1 signaling was essential for attracting C1q synaptic deposition then apposition of phagocytic microglia, ensuing synaptic loss and neurological disease. Minocycline-deactivated microglia, antibody-blocked C1q, or neuronal Nr4a1 restore protected lupus mice from synapse loss and NP manifestations. Our findings revealed an active role of neurons in coordinating microglia-mediated synaptic loss and highlight neuronal Nr4a1 and C1q as critical components amenable to pharmacological intervention.

2022-02-23 | GSE154288 | GEO

Microglia contributes to bipolar depression through Serinc2-dependent phospholipid synthesis

Project description:<p>Although clinical research has revealed microglia-related inflammatory and immune responses in bipolar disorder (BD) patient brains, it remains unclear how microglia contribute to the pathogenesis of BD. Here, we demonstrated that Serinc2 is associated with susceptibility to BD and showed a reduced expression in BDII patient plasma, which correlated with the disease severity. Using induced pluripotent stem cell (iPSC) models of sporadic and familial BDII patients, we found that Serinc2 expression showed deficits in iPSC-derived microglia-like cells, resulting in decreased synaptic pruning. Further, combining the microglia-specific Serinc2-deficient mouse and iPSC-microglia models, we found that microglial Serinc2 deficits functioned through attenuating the synthesis of serine-related phospholipids in the plasma membrane, thus resulting in depression-like behavioral abnormalities in the animals. Finally, we showed that the Serinc2-dependent lipid deficits diminished microglial membrane CR3 formation to interrupted synaptic pruning signals from neurons. Therefore, our results indicated that Serinc2 deficits in microglia might contribute to the pathogenesis of BD.</p>

2025-08-27 | MTBLS12830 | MetaboLights

Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation

Project description:Microglia repair injury and maintain homeostasis in the brain, but whether aberrant microglial activation can contribute to neurodegeneration remains unclear. Here, we use transcriptome profiling to demonstrate that deficiency in frontotemporal dementia (FTD) gene progranulin (Grn) leads to an age-dependent, progressive up-regulation of lysosomal and innate immunity genes, increased complement production, and synaptic pruning activity in microglia. During aging, Grn-/- mice show profound accumulation of microglia and preferential elimination of inhibitory synapses in the ventral thalamus, which contribute to hyperexcitability in the thalamocortical circuits and obsessive-compulsive disorder (OCD)-like grooming behaviors. Remarkably, blocking complement activation by deleting C1qa gene significantly reduces synaptic pruning by Grn-/- microglia, and mitigates neurodegeneration, behavioral phenotypes and premature mortality in Grn-/- mice. These results uncover a previously unrecognized role of progranulin in suppressing microglia activation during aging, and support the idea that blocking complement activation is a promising therapeutic target for neurodegeneration caused by progranulin deficiency. Gene expression study in multiple brain regions from a mouse model of progranulin deficiency Please note that 9 outlier samples were excluded from data analysis. Therefore, there are 326 raw data columns (i.e. 163 samples) in the non_normalized data matrix while 154 samples are represented here.

2016-03-31 | E-GEOD-75083 | biostudies-arrayexpress

Maternal SARS-CoV-2 impacts fetal placental macrophage programs and placenta-derived microglial models of neurodevelopment

Project description:Using single-cell RNA-sequencing, we demonstrated that HBC subpopulations exhibit distinct cellular programs, with specific subpopulations differentially impacted by SARS-CoV-2. Assessment of differentially expressed genes implied impaired phagocytosis, a key function of both HBCs and microglia, in some subclusters. Leveraging previously validated models of microglial synaptic pruning, we showed that HBCs isolated from placentas of SARS-CoV-2 positive pregnancies can be transdifferentiated into microglia-like cells (HBC-iMGs), with impaired synaptic pruning behavior compared to HBC models from negative controls.

2024-11-01 | GSE270321 | GEO

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data