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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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			Action	DRS
	SRR26713056_1.fastq.gz	Fastqsanger.gz
	SRR26713056_2.fastq.gz	Fastqsanger.gz
	SRR26713057_1.fastq.gz	Fastqsanger.gz
	SRR26713057_2.fastq.gz	Fastqsanger.gz
	SRR26713058_1.fastq.gz	Fastqsanger.gz

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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.

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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.

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