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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PROVIDER: PRJNA1151598 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
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| 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: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:This SuperSeries is composed of the SubSeries listed below.
2025-03-05 | GSE275564 | 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.
2013-02-28 | GSE26532 | GEO
Project description:IntroductionGrowing recognition of microglia's role in neurodegenerative disorders has accentuated the need to characterize microglia profiles and their influence on pathogenesis. To understand changes observed in the microglial profile during the progression of synucleinopathies, microglial gene expression and DNA methylation were examined in the mThy1-α-synuclein mouse model.MethodsDisease progression was determined using behavioral tests evaluating locomotor deficits before DNA and RNA extraction at 7 and 10 months from isolated microglia for enzymatic methyl-sequencing and RNA-sequencing.ResultsPathway analysis of these changes at 7 months indicates a pro-inflammatory profile and changes in terms related to synaptic maintenance. Expression and methylation at both 7 and 10 months included terms regarding mitochondrial and metabolic stress. While behavior symptoms progressed at 10 months, we see many previously activated pathways being inhibited in microglia at a later stage, with only 8 of 53 shared pathways predicted to be directionally concordant. Despite the difference in pathway directionality, 21 of the 22 genes that were differentially expressed and annotated to differentially methylated regions at both 7 and 10 months had conserved directionality changes.DiscussionThese results highlight a critical period in disease progression, during which the microglia respond to α-synuclein, suggesting a transition in the role of microglia from the early to late stages of the disease.
| S-EPMC11865073 | biostudies-literature
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.
2010-07-22 | GSE19534 | GEO