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:Microglia are increasingly recognized as active drivers of Parkinson's disease (PD), contributing to neuroinflammation, α-synuclein clearance, and dopaminergic neuron loss. Because aging is the strongest risk factor for PD and independently shifts microglia toward a primed, pro-inflammatory state, disentangling age- and disease-related transcriptional programs is essential. Aim and workflow This dataset profiles the bulk transcriptome of microglia from [PD model] and control mice at [young] and [old] ages (2×2 design) to resolve disease, age, and interaction effects. Brains were enzymatically dissociated, microglia isolated by MACS using CD11b MicroBeads, and total RNA extracted for bulk RNA-seq library preparation and sequencing on Novaseq 6000. n = 3-4 per group. Both sexes included. All samples except Sample1 includes two mice. Sequencing was done with a target of 40G per sample PE150.
2026-06-17 | E-MTAB-17136 | biostudies-arrayexpress
Project description:The accumulation of misfolded α-synuclein and the loss of dopaminergic neurons are hallmarks of Parkinson’s disease (PD), contributing to the development of synucleinopathies. Although considerable progress has been made in understanding α-synuclein's role in PD pathology, the precise mechanisms involved remain unclear. Human midbrain organoids (hMOs) have emerged as valuable models for studying PD, yet the lack of microglia limits the ability to investigate neuroimmune interactions. Recent studies show that integrating microglia into hMOs enhances neuronal maturation and functionality. Here, we generated a human midbrain assembloid model by incorporating iPSC-derived microglia into midbrain organoids from healthy control individuals and a PD patient carrying the SNCA triplication (3xSNCA) mutation. Our results show that 3xSNCA microglia alone are sufficient to induce early, endogenous formation of phosphorylated α-synuclein (pS129) pathology in the absence of exogenous fibril seeding. This PD-pathology emerged as early as day 50 of culture and was not observed in models lacking microglia. These findings highlight a critical role for patient-derived microglia in driving α-synuclein pathology and provide a physiologically relevant platform for studying early neuroimmune mechanisms in PD and testing potential therapeutic strategies.
2026-06-05 | GSE299260 | 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:Parkinson’s disease microglia induce endogenous α-synuclein pathology in patient specific midbrain organoids.
| PRJNA1273175 | ENA
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: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:The etiology of Parkinson’s disease (PD) remains elusive, and the limited availability of suitable animal models hampers research on pathogenesis and drug development. We report the development of a cynomolgus monkey model of PD that combines AAV-mediated overexpression of α-synuclein into the substantia nigra with injection of Poly(ADP-ribose) (PAR) into the striatum. Our results show that pathological processes were accelerated, including dopaminergic neuron degeneration, Lewy Bodies aggregation, and hallmarks of inflammation in microglia and astrocytes. Behavioral phenotypes, dopamine transporter imaging and transcriptomic profiling further demonstrate consistencies between the model and PD patients. This model can help to determine mechanisms underlying PD impacted by α-synuclein and PAR and aid in accelerated development of therapeutic strategies for PD.
2024-09-20 | GSE276753 | GEO