Single-cell RNA-seq of mouse dopaminergic neurons informs candidate gene selection for sporadic Parkinson disease
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Abstract
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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The single-cell classification studies identified partially overlapping dopamine neuron subtypes, some of which were located in a manner agnostic to traditional anatomical boundaries.
“Although these studies differed significantly in their experimental parameters and analysis methods, they identified partially overlapping subtypes, some of which were located in a manner agnostic to traditional anatomical boundaries (SN, VTA, & RR).”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [16]
Molecular heterogeneity within the murine dopaminergic system has been investigated by at least six independent groups, all attempting to classify dopamine neurons based on gene expression.
“Molecular heterogeneity within the murine DAergic system has been investigated by at least six independent groups, all attempting to classify DA neurons based on gene expression [13–18].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [16]
Vip+ dopamine neurons have an mRNA signature of Vip+, Gipr+, Calb1+, Sox6-, and Aldh1a1-.
“Based on the concordance of other genes co-expressed in Vip+ neurons [13–16], we developed the following mRNA signature for Vip neurons: Vip+ [13–16], Gipr+ [15], Calb1+ [13,14], Sox6- [13,14], Aldh1a1- [13,14].”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [16]
Hook et al. identified two embryonic DA neuron types, E15.MB.1 and E15.MB.2; one corresponded to a neuroblast population and the other to a more mature DA neuron.
“By contrast, [16] identified only two embryonic types (E15.MB.1 and E15.MB.2) representing a neuroblast population and a more mature DA neuron.”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [16]
A Vglut2+, Calb1+ dopamine population is represented in at least three studies and is ambiguous, likely encompassing two or more distinct populations.
“Vglut2+,Calb1+ DA neurons are ambiguous and likely encompass two or more distinct populations”
From Classification of midbrain dopamine neurons using single-cell gene expression profiling approaches (2020) · cites this paper as [16]
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“Previous studies mostly perform scRNA seq in younger mice, while single nucleus RNA sequencing is more common in adult mice (Hook et al., 2018; Loo et al., 2019; Zeisel et al., 2015; Zhou et al., 2020).”
- Authors
- Hook, P. W., McClymont, S. A., Cannon, G. H., Law, W. D., Morton, A. J., Goff, L. A., & McCallion, A. S.
- Affiliations
- Johns Hopkins University (US)
- University of Cambridge (GB)
- Corresponding author
- Goff, Loyal A.
- McCallion, Andrew S.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2018-03
- Volume
- 102
- Issue
- 3
- Pages
- 427-446
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5985341
- OpenAlex
- W2623843598
- Cited by
- 136
- References
- 108
- Citations by year
- 2026: 6 · 2025: 11 · 2024: 25 · 2023: 18 · 2022: 19 · 2021: 20 · 2020: 18 · 2019: 11 · 2018: 8
- FWCI
- 9.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Apollo (University of Cambridge) (submittedVersion)
- Apollo
- Funders
- National Institutes of Health (R01 NS62972, MH106522)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- sporadic Parkinson disease, dopaminergic neurons, substantia nigra, nigrostriatal pathway, candidate gene prioritization, single-cell RNA sequencing, mouse embryo development, genetic susceptibility loci
- MeSH terms
- Animals, Cell Separation, Genetic Markers, Parkinson Disease, Substantia Nigra, Sequence Analysis, RNA, Mice, Knockout, Gene Regulatory Networks, Genome-Wide Association Study, Genetic Loci, Genetic Association Studies, Single-Cell Analysis, Dopaminergic Neurons
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