Deciphering Motor Dysfunction and Microglial Activation in mThy1-α-Synuclein Mice: A Comprehensive Study of Behavioral, Gene Experssion, and Methylation Changes [RNA-Seq]
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ABSTRACT:
PROVIDER: PRJNA1151598 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR30350937_1.fastq.gz | Fastqsanger.gz | |||
| SRR30350937_2.fastq.gz | Fastqsanger.gz | |||
| SRR30350938_1.fastq.gz | Fastqsanger.gz | |||
| SRR30350938_2.fastq.gz | Fastqsanger.gz | |||
| SRR30350939_1.fastq.gz | Fastqsanger.gz |
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Project description:Deciphering Motor Dysfunction and Microglial Activation in mThy1-α-Synuclein Mice: A Comprehensive Study of Behavioral, Gene Experssion, and Methylation Changes
| PRJNA1151679 | ENA
Project description:Deciphering Motor Dysfunction and Microglial Activation in mThy1-α-Synuclein Mice: A Comprehensive Study of Behavioral, Gene Experssion, and Methylation Changes [Enzymatic Methyl-Seq]
| PRJNA1151599 | ENA
Project description:BACKGROUND: Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. However, the influence α-syn has on DNA methylation and gene expression patterns for other genes has not been thoroughly explored. Our objective is to determine gene expression and methylation changes in microglia induced by aggregate α-syn. METHODS: Transgenic mThy1-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 7 and 10-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-induced changes in gene expression and genomic methylation were determined and examined for pathway and functional enrichment. RESULTS: Microglial DNA isolated from our 7-month cohort had 6,712 differentially methylated regions (DMR), while RNA levels demonstrated a change in 1,141 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 7-month DEGs and DMRs were highly associated with neuroinflammation likely via TLR pathways. We observed 8,531 DMRs and 1,686 DEGs in 10-month mThy1-Asyn mice. These genes were often predicted by Ingenuity Pathway Analysis to demonstrate inhibition of previously activated inflammatory pathways at 7 months. CONCLUSION: We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.
2025-03-05 | GSE275510 | GEO
Project description:BACKGROUND: Synucleinopathy disorders are characterized by aggregates of α-synuclein (α-syn), which engage microglia to elicit a neuroinflammatory response. However, the influence α-syn has on DNA methylation and gene expression patterns for other genes has not been thoroughly explored. Our objective is to determine gene expression and methylation changes in microglia induced by aggregate α-syn. METHODS: Transgenic mThy1-Asyn mice overexpressing human α-syn are a model of synucleinopathy. Microglia from 7 and 10-month-old mice were used to isolate nucleic acids for methylated DNA and RNA-sequencing. α-Syn-induced changes in gene expression and genomic methylation were determined and examined for pathway and functional enrichment. RESULTS: Microglial DNA isolated from our 7-month cohort had 6,712 differentially methylated regions (DMR), while RNA levels demonstrated a change in 1,141 differentially expressed genes (DEGs) between mThy1-Asyn mice and wild-type littermate controls. The 7-month DEGs and DMRs were highly associated with neuroinflammation likely via TLR pathways. We observed 8,531 DMRs and 1,686 DEGs in 10-month mThy1-Asyn mice. These genes were often predicted by Ingenuity Pathway Analysis to demonstrate inhibition of previously activated inflammatory pathways at 7 months. CONCLUSION: We observed significant α-syn-induced methylation and gene expression changes in microglia. Our data suggest that α-syn overexpression initiates microglial activation leading to neuroinflammation and cellular metabolic stresses, which is associated with disease progression.
2025-03-05 | GSE275511 | GEO
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:Synucleinopathies are age-related neurological disorders which include dementia with Lewy bodies (DLB), Parkinson’s disease (PD), and multiple system atrophy (MSA). The diseases are characterized by the abnormal deposition and aggregation of a-synuclein and neuroinflammation. Recent studies have demonstrated the existence of structurally distinct a-synuclein aggregates in this group of the diseases. While the correlation between specific forms of a-synuclein and distinct pathological characteristics has been extensively studied, their relationship to neuroinflammation remains elusive. Here, we examined the effects of structurally distinct a-synuclein polymorphs on microglial neuroinflammation. Human induced pluripotent stem cells (iPSCs)-derived microglia (iMicroglia) were treated with a-synuclein polymorphs including EGCG stabilized a-synuclein oligomers (EO), kinetically stable a-synuclein oligomers (KSO), dopamine stabilized a-synuclein oligomers (DO), a-synuclein preformed fibrils (PFF), sonicated a-synuclein preformed fibrils (sPFF), and matured a-synuclein fibrils (Fib). Microglial gene expressions were accessed by transcriptome analysis and Toll-like receptor agonist activities were determined by HEK-Blue TLR reporter assay. Exposures to kinetically stable a-synuclein oligomers and matured a-synuclein fibrils induced the expression of microglial cytokines and chemokines, while other species did not. Microglial transcriptome analysis yielded that all polymorphs commonly induce toll-like receptor (TLR) signaling cascade despite differential transcriptomic phenotypes. Among structurally distinct a-synuclein polymorphs, live cell TLR reporter assay showed that kinetically stable a-synuclein oligomers induce the activities of TLR2 and 4, and sonicated a-synuclein preformed fibril TLR4, relative to the control. These results suggest that structurally distinct a-synuclein polymorphs have likewise distinct neuroinflammatory properties.
2026-01-21 | GSE305401 | GEO
Project description:Alpha-synuclein is an abundant protein implicated in synaptic function and plasticity, but the molecular mechanism of its action is not understood. Missense mutations and gene duplication/triplication events result in Parkinson's disease, a neurodegenerative disorder of old age with impaired movement and emotion control. Here, we systematically investigated the striatal as well as the cerebellar transcriptome profile of alpha-synuclein-deficient mice via a genome-wide microarray survey in order to gain hypothesis-free molecular insights into the physiological function of alpha-synuclein. A genotype-dependent, specific and strong downregulation of forkhead box P1 (Foxp1) transcript levels was observed in all brain regions from postnatal age until old age and could be validated by qPCR. In view of the co-localization and heterodimer formation of FOXP1 with FOXP2, a transcription factor with a well established role for vocalization, and the reported regulation of both alpha-synuclein and FOXP2 expression during avian song learning, we performed a detailed assessment of mouse movements and vocalizations in the postnatal period. While there was no difference in isolation-induced behavioral activity in these animals, the alpha-synuclein-deficient mice exhibited an increased production of isolation-induced ultrasonic vocalizations (USVs). This phenotype might also reflect the reduced expression of the anxiety-related GABA-A receptor subunit gamma 2 (Gabrg2) we observed. Taken together, we identified an early behavioral consequence of alpha-synuclein deficiency and accompanying molecular changes, which supports the notion that the neural connectivity of sound or emotion control systems is affected. Factorial design comparing SNCA knock-out mice with wild type littermates in two different tissues (striatum, cerebellum) at two different timepoints (6 and 21 month)
2010-07-21 | E-GEOD-19534 | 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:A growing body of evidence suggests that nuclear alpha-synuclein (aSyn) plays a role in the pathogenesis of Parkinson’s disease (PD). However, this question has been difficult to address as controlling the localization of aSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered Snca-NLS mice which localize endogenous aSyn to the nucleus. We characterized these mice on a behavioral, histological, and biochemical level to determine whether the increase of nuclear aSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to aSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of Snca-NLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signalling, including Darpp32, Pde10a, and Gng7, which we further confirmed was decreased in cortical samples of the Snca-NLS mice compared to controls. These results suggest that chronic endogenous nuclear aSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of aSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.
2022-04-06 | PXD032065 | Pride
Project description:Rett Syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl-CpG-binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here we combine transcriptomic and behavioral assays to assess baseline and stimulus-evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5-7 days post-fertilization (dpf). We show that zebrafish mecp2 function is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA-seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2’s function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.
2024-01-01 | GSE252307 | GEO