Single-cell RNA-seq of mouse dopaminergic neurons informs candidate gene selection for sporadic Parkinson's disease
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA422247 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6372100_1.fastq.gz | Fastqsanger.gz | |||
| SRR6372100_2.fastq.gz | Fastqsanger.gz | |||
| SRR6372110_1.fastq.gz | Fastqsanger.gz | |||
| SRR6372110_2.fastq.gz | Fastqsanger.gz | |||
| SRR6372120_1.fastq.gz | Fastqsanger.gz |
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Project description:Genetic variation modulating risk of sporadic Parkinson’s disease (PD) has been primarily explored through genome wide association studies (GWAS). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal timepoints. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a novel postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including known PD genes and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1 null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.
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Project description:Genetic variation modulating risk of sporadic Parkinson disease (PD) has been primarily explored through genome-wide association studies (GWASs). However, like many other common genetic diseases, the impacted genes remain largely unknown. Here, we used single-cell RNA-seq to characterize dopaminergic (DA) neuron populations in the mouse brain at embryonic and early postnatal time points. These data facilitated unbiased identification of DA neuron subpopulations through their unique transcriptional profiles, including a postnatal neuroblast population and substantia nigra (SN) DA neurons. We use these population-specific data to develop a scoring system to prioritize candidate genes in all 49 GWAS intervals implicated in PD risk, including genes with known PD associations and many with extensive supporting literature. As proof of principle, we confirm that the nigrostriatal pathway is compromised in Cplx1-null mice. Ultimately, this systematic approach establishes biologically pertinent candidates and testable hypotheses for sporadic PD, informing a new era of PD genetic research.
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Project description:First, we differentiated human iPSCs into dopaminergic neurons. To reproduce and to study sporadic PD, the cells were subsequently exposed to increasing concentrations of the neurotoxin MPP+, which is considered the standard for experimentally inducing Parkinsonism. Resulting cells were examined using temporal transcriptomics analysis at various time-points after 24h of exposure. The transcriptomics analysis revealed a strong time- and dose-dependent response with genes overrepresented across pathways involved in PD etiology such as “Parkinson’s Disease”, “Dopaminergic signaling” and “calcium signaling”.
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