Rattus norvegicus
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ABSTRACT:
PROVIDER: PRJNA136651 | ENA |
REPOSITORIES: ENA
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Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases. We collected culture media from differentiated SH-SY5Y cells overexpressing either human a-synuclein (alpha-SCM) or beta-galactosidase (LZCM) and treat these media to primary rat microglia at the concentration of a-synuclein of 1.1M. Transcriptome analyses with microglial cells treated with either aSCM or LZCM at two different time points, 6 h and 24 h.
2013-02-28 | E-GEOD-26532 | biostudies-arrayexpress
Project description:Abnormal accumulation of aggregated proteins and sustained microglial activation are important contributors of neurodegenerative process in neurological diseases. Recent studies have shown that aggregation-prone proteins, such as a-synuclein, the protein implicated in Parkinson’s disease (PD), are released from neuronal cells and thus present in the extracellular fluid, pointing to the possible paracrine effects of these proteins on microglial immune responses. However, the mechanism underlying the disease-associated microglial activation and the role of neuronal proteins in this process remain unknown. Here, we show that extracellular a-synuclein released from neuronal cells is an endogenous ligand of toll-like receptor 2 (TLR2) and activates microglia, which in turn induces neurodegeneration. Interaction between neuron-released a-synuclein and TLR2 and subsequent activation of the TLR2 signaling were demonstrated comprehensively by using computational modeling of signaling network and by the experimental validation in TLR2-deficient microglia both in vitro and in vivo. In contrast to the neuron-released a-synuclein, recombinant a-synuclein proteins, including monomer, oligomer, fibril, or nitrated forms, were not able to interact or activate TLR2, suggesting that neuronal cells have a mechanism of enriching specific forms of a-synuclein capable of activating TLR2 during the process of releasing this protein. Taken together, the results suggest that both neuron-released extracellular a-synuclein and TLR2 might be novel therapeutic targets for modifying neuroinflammation in PD and related neurodegenerative diseases.
2013-02-28 | GSE26532 | GEO
Project description:We report the exchange of alpha-synuclein aggregates from one cell to another and examined transcriptomic changes following protein exchange. Differential expression (DE) analysis comparing alpha-synuclein-treated with untreated microglia identified alpha-synuclein induceable genes which were linked to inflammation, apoptosis, ER stress and intracellular protein targeting, while downregulated genes included categories related to mitosis, cytoskeleton and vesicle mediated transport. Co-culturing alpha-synuclein treated with untreated microglia largely suppressed the inflammatory and apoptotic phenotype of microglia thereby rescuing cells from cell death. Most importantly, these transprictomic changes were prevented by co-culturing the cells without direct cell-cell contact (transwell).
2021-09-28 | GSE166127 | GEO
Project description:Neuroinflammatory processes are a prominent contributor to the pathology of Parkinson’s disease (PD), characterized by the progressive loss of dopaminergic neurons in the substantia nigra (SN) and deposits of α-synuclein aggregates. MLKL-mediated cell necroptosis might occur in the onset of PD and lead to neuronal dopaminergic degeneration. However, the link between α-synuclein, neuroinflammatory processes, and neurodegeneration in PD remains unclear. Here, our in vitro study indicated that inhibition of MLKL exerted a protective effect against 6-OHDA- and TNF-α-induced neuronal cell death. Furthermore, we created a mouse model (Tg-Mlkl-/-) with typical progressive Parkinson traits by crossbreeding SNCA A53T transgenic mice with MLKL knockout mice. Tg-Mlkl-/ mice displayed dramatically improved motor symptoms and reduced hyperphosphorylated α-synuclein expression. More data suggested that MLKL deficiency protected dopaminergic neurons, blocked neuronal cell death, and attenuated neuroinflammation by inhibiting the activation of the microglia and astrocytes. Single-cell RNA-seq analysis revealed reduced microglial cells and damped neuron death in the SN of the Tg-Mlkl-/- mice. Subcluster analysis identified a unique cell type-specific transcriptome profiling in the MLKL deficiency mice. Thus, MLKL represents a critical therapeutic target for reducing neuroinflammation and preventing dopaminergic neuron degeneration.
2023-12-14 | GSE197679 | GEO
Project description:In murine glioma models, TLR2 is selectively upregulated in glioma-associated microglia. We found that TLR2 activation led to down-regulation of MHC-II in microglia. Therefore, we examined the effect of TLR2 activation on IFN-gamma-induced microglial transcriptome by in vitro culture of murine adult microglia. In the study, we confirmed that TLR2 activation led to Ciita shutdown and inhibition of MHC-II related genes, which also revealed the role of TLR2 in inducing APC disability and tumor immune escape. In addition, this work can be used to reveal the transcriptional characteristics of murine microglia during IFN-gamma and TLR2 activation.
2018-09-25 | GSE109297 | GEO
Project description:We report the exchange of alpha-synuclein aggregates from one cell to another and examined transcriptomic changes following protein exchange. By obtaining 12,461 genes from isolated RNA samples, we performed differential expression analysis and generated gene ontology enrichment and network analysis. Differential expression (DE) analysis comparing alpha-synuclein-treated with untreated microglia identified 687 upregulated and 1502 downregulated genes. Upregulated genes were linked to inflammation, apoptosis, ER stress and intracellular protein targeting, while downregulated genes included categories related to mitosis, cytoskeleton and vesicle mediated transport. Co-culturing alpha-synuclein treated with untreated microglia largely suppressed the inflammatory and apoptotic phenotype of microglia thereby rescuing cells from cell death.
2021-09-28 | GSE152100 | GEO
Project description:Although α-synucleinis implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels of α-synuclein assemblies are toxic and how they cause progressive loss of human dopaminergic neurons. To address this issue, we used iPSC-derived dopaminergic neurons with a-synuclein triplication or controls where endogenous α-synuclein was imprinted into synthetic or disease-relevant conformations. We used α-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) .We found that a 2.5-fold increase in α-synuclein levels in α-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in α-synuclein gene expression.Transcriptomic analysis and isogenic correction of α-synuclein triplication revealed that intraneuronal α-synuclein levels solely and sufficiently explained vulnerability to cell death.
2020-09-02 | GSE149632 | GEO
Project description:Alpha-synuclein aggregates (αSynAgg) are pathological hallmarks of Parkinson’s disease (PD) that induce microglial activation and immune-mediated neurotoxicity, although the molecular mechanisms of αSynAgg-induced immune activation are poorly defined. We used mass spectrometry to define proteomic changes induced by αSynAgg using in-vitro mouse microglia and an in-vivo fly (Drosophila melanogaster) model with neuron-specific αSyn overexpression. In mouse microglia, αSynAgg induced robust pro-inflammatory activation (increased expression of 864 genes including Irg1, Ifit1 and Pyhin) and increased nuclear proteins involved in RNA synthesis, splicing and anti-viral defense mechanisms. Conversely, αSynAgg decreased expression of 530 proteins (including Cdc123, Sod1 and Grn), which were predominantly cytosolic and involved in antigen presentation as well as metabolic, proteosomal and lysosomal mechanisms. Pathway analyses and confirmatory in -vitro studies suggested that αSynAgg partly mediates its effects via Stat3 activation. 26 proteins differentially-expressed by αSynAgg were also identified as PD risk genes in genome-wide association studies (upregulated: Brd2, Clk1, Siglec1; down-regulated: Memo1, Arhgap18, Fyn and PGgrn/Grn). We then validated progranulin (PGrn/Grn) as a lysosomal PD-associated protein that is decreased in striatal and nigral microglia in post-mortem PD brain compared to non-disease controls, congruent with our in -vitro findings.
2020-01-24 | PXD013691 | Pride
Project description:Tight immune defense against environment and a unique ability of self-repair are the hallmarks of epithelia. Here we show that innate immunity Toll like receptor 2 (TLR2) coordinates these key functions thereby promoting hair growth and tissue regeneration. TLR2 is enriched in hair follicle stem cells (HFSCs) and its levels change in hair cycle and skin disorders. The lack of TLR2 in HFSCs diminishes activation and proliferation of HFSCs markedly prolonging the resting phase of hair cycle. Transcriptome profiling of HFSCs revealed that TLR2 regulates main hair regeneration pathways. TLR2 deletion upregulates inhibitory BMP7 signaling, while the blockade by Noggin restores deficient HFSCs proliferation in the absence of TLR2. In injury model TLR2 is required for both, tissue and hair regeneration. While endothelial TLR2 drives wound revascularization and closure, HFSC TLR2 controls hair regrowth. Endogenous TLR2 ligand produced in hair follicles promotes hair regeneration and growth via HFSC TLR2. Together, HFSC TLR2 drives stem cell proliferation, hair cycle and regeneration.
2024-01-04 | GSE179300 | GEO
Project description:Inflammation is a common feature in neurodegenerative diseases that participates in the process of neuronal loss. Here, we questioned whether the inflammatory reaction generated in Parkinson´s disease (PD) by dopaminergic neuron degeneration would trigger specific inflammatory reactions in the midbrain and in the striatum that could modify the course of neuronal death. Experimental parkinsonism was induced by overexpressing α-synuclein in the substantia nigra with a viral vector. Bulk RNA sequencing of purified midbrain microglia/myeloid cells showed a phagocytic and anti-inflammatory M2 phenotype, while midbrain astrocytes presented a pro-inflammatory state. In the striatum, microglia but not astrocytes presented a pro-inflammatory state.
2021-12-19 | GSE191131 | GEO