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Transcriptomic insights into Multiple System Atrophy from a PLP-α-Synuclein transgenic mouse model

ABSTRACT: Transcriptomic insights into Multiple System Atrophy from a PLP-α-Synuclein transgenic mouse model

PROVIDER: PRJNA1036728 | ENA |

REPOSITORIES: ENA

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Transcriptomic insights into Multiple System Atrophy from a PLP-α-Synuclein transgenic mouse model

Project description:Multiple system atrophy (MSA) is a rare, neurodegenerative disorder with rapid motor and non-motor symptom progression. MSA is characterized by protein aggregations of α-synuclein found in the cytoplasm of oligodendrocytes. Despite this pathological hallmark, there is still little known about the cause of this disease, resulting in poor treatment options and quality of life post-diagnosis. In this study, we investigated differentially expressed genes via RNA-sequencing of brain samples from a validated PLP-α-synuclein transgenic mouse model, identifying a total of 40 DEGs in the MSA group compared to control, with top detected genes being Gm15446, Mcm6, Aldh7a1 and Gm3435. We observed a significant enrichment of immune pathways and endothelial cell genes among the upregulated genes, whereas downregulated genes were significantly enriched for oligodendrocyte and neuronal genes. We then calculated possible overlap of these DEGs with previously profiled human MSA RNA, resulting in the identification of significant downregulation of the Tsr2 gene. Identifying key gene expression profiles specific to MSA patients is crucial to further understanding the cause, and possible prevention, of this rapidly progressive neurodegenerative disorder.

2024-11-07 | GSE247259 | GEO

Phenotypic manifestation of alpha-synuclein strains derived from Parkinson’s disease and multiple system atrophy in human dopaminergic neurons

Project description:Althougha-synuclein is implicated in the pathogenesis of Parkinson’s disease and related disorders, it remains unclear whether specific conformations or levels ofa-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 a-synuclein was imprinted into synthetic or disease-relevant conformations. We used a-synuclein fibrils generated de novo or amplified from homogenates of brains affected with Parkinson’s disease (n=3) or multiple system atrophy (n=5). We found that a 2.5-fold increase in a-synuclein levels in a-synuclein gene triplication neurons promoted seeded aggregation in a dose and time-dependent fashion, which was associated with a further increase in a-synuclein gene expression. Progressive neuronal loss was observed only in a-synuclein triplication neurons seeded with brain-amplified fibrils. Transcriptomic analysis and isogenic correction of a-synuclein triplication revealed that intraneuronalalpha-synuclein levels solely and sufficiently explained vulnerability to neuronal death

2021-04-13 | GSE171999 | GEO

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

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

Distinct microglia subsets are associated with α-synucleinopathy in multiple system atrophy

Project description:We developed a novel mice model of multiple system atrophy (MSA)-cerebellar type (MSA-C) by over-expression of human mutant α-synuclein (α-syn) in oligodendrocyte using Tet-off system. We identified distinct microglial subpopulations in a novel MSA-C model mice.

2022-09-06 | GSE209944 | GEO

The expression profiling of the early stage of multiple system atrophy model mice

Project description:Global transcriptional analysis of the brain of multiple system atrophy model mice after synuclein induction by tamoxifen. Multiple system atrophy (MSA) is pathologically characterized by accumulation of phosphorylated α-synuclein in the oligodendrocytes. The pathophisiological mechinism under the early staige of disease pregression has been unknown. To clarify molecular alteration just after α-synuclein overexpression in the oligodendrocytes, we performed whole transcriptome analysis of the brain obtained from MSA model mice and control at 10 days after α-synuclein induction.

2021-06-01 | GSE129531 | GEO

Hsp110 Mitigates α-Synuclein Pathology In Vivo

Project description:Parkinson’s disease is characterized by the aggregation of the presynaptic protein α-synuclein and its deposition into pathologic Lewy bodies. While extensive research has been carried out on mediators of α-synuclein aggregation, molecular facilitators of α-synuclein disaggregation are still generally unknown. We investigated the role of molecular chaperones in both preventing and disaggregating α-synuclein oligomers and fibrils, with a focus on the mammalian disaggregase complex. Here, we show that overexpression of the chaperone Hsp110 is sufficient to reduce α-synuclein aggregation in a mammalian cell culture model. Additionally, we demonstrate that Hsp110 effectively mitigates α-synuclein pathology in vivo through the characterization of transgenic Hsp110 and double transgenic α-synuclein/Hsp110 mouse models. Unbiased analysis of the synaptic proteome of these mice revealed that overexpression of Hsp110 can override the protein changes driven by the α-synuclein transgene. Furthermore, overexpression of Hsp110 is sufficient to prevent endogenous α-synuclein templating and spread following injection of aggregated α-synuclein seeds into brain, supporting a role for Hsp110 in the prevention and/or disaggregation of α-synuclein pathology.

2020-05-26 | PXD016015 | Pride

microRNA profiling by high-throughput sequencing in the substantia nigra and striatum of Multiple System Atrophy (MSA) transgenic mice and wild type controls

Project description:Multiple system atrophy (MSA) is a fatal rapidly progressive Ia-synucleinopathy, characterized by prominent Ia-synuclein accumulation in oligodendrocytes. In this study we investigated miRNA expression in the substantia nigra and striatum of MSA transgenic mice (Tg(Plp1-SNCA)1Haa) and wild type controls. This forms part of a larger study in which we investigated miRNA-mRNA regulatory network in substantia nigra and striatum of MSA transgenic mice in pre-motor stage of neurodegenration.

2016-03-15 | E-MTAB-3993 | biostudies-arrayexpress

Failure of diet-induced transcriptional adaptations in A30P alpha-synuclein transgenic mice

Project description:Failure of diet-induced transcriptional adaptations in A30P alpha-synuclein transgenic mice

| PRJNA810724 | ENA

Progranulin–glucocerebrosidase complex regulates tau and alpha-synuclein inclusions to alter phenotypes in tauopathy

Project description:Many neurodegenerative disorders including Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) are characterized by abnormal protein deposition and frequently show comorbid pathology. Progranulin (PGRN) is implicated not only in TDP-43 but in tau and alpha-synuclein proteinopathies. However, the underlying mechanisms are unknown. Here, we generated P301S tau transgenic mice with PGRN haploinsufficiency and loss and found that those mice exhibit exacerbated disinhibition phenotype while showing attenuated memory impairment, hippocampal atrophy, and transcriptomic changes. Remarkably, the phenotypic alteration was accompanied by an increase in tau inclusions, which are positive for alpha-synuclein, a PGRN binding partner beta-glucocerebrosidase (GCase), and its substrate glucosylceramide. GCase inhibition or PGRN deficiency enhanced tau aggregation induced by AD-derived tau seeds in neurons. In vitro, GCase and glucosylceramide promoted P301S tau aggregation. Similar co-pathology was observed in AD and FTLD-GRN patients.

2024-01-18 | GSE180672 | GEO

Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

Project description:Phenotypic manifestation of alpha-synuclein strains from Parkinson’s disease and multiple system atrophy in human dopaminergic neruons

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