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Cited by 552Parkinson's Disease Mechanisms and TreatmentsSingle-cell and spatial transcriptomicsNuclear Receptors and Signaling

Single-cell genomic profiling of human dopamine neurons identifies a population that selectively degenerates in Parkinson’s disease

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Kamath, Tushar, Abdulraouf, Abdulraouf, Burris, S. J., Langlieb, Jonah, Gazestani, Vahid, Nadaf, Naeem M., Balderrama, Karol, Vanderburg, Charles +1 more·2022·Nature Neuroscience
DOI 10.1038/s41593-022-01061-1PMC PMC9076534
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Abstract

The loss of dopamine (DA) neurons within the substantia nigra pars compacta (SNpc) is a defining pathological hallmark of Parkinson’s disease (PD). Nevertheless, the molecular features associated with DA neuron vulnerability have not yet been fully identified. Here, we developed a protocol to enrich and transcriptionally profile DA neurons from patients with PD and matched controls, sampling a total of 387,483 nuclei, including 22,048 DA neuron profiles. We identified ten populations and spatially localized each within the SNpc using Slide-seq. A single subtype, marked by the expression of the gene AGTR1 and spatially confined to the ventral tier of SNpc, was highly susceptible to loss in PD and showed the strongest upregulation of targets of TP53 and NR2F2 , nominating molecular processes associated with degeneration. This same vulnerable population was specifically enriched for the heritable risk associated with PD, highlighting the importance of cell-intrinsic processes in determining the differential vulnerability of DA neurons to PD-associated degeneration.

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  • Single-cell RNA sequencing has revealed distinct microglial and astrocytic subpopulations, such as disease-associated microglia and reactive astrocytes, which are involved in plaque clearance, neuroinflammation, and synaptic modulation.

    “This technique has revealed distinct microglial and astrocytic subpopulations, such as disease-associated microglia (DAM) and reactive astrocytes, which are involved in plaque clearance, neuroinflammation, and synaptic modulation118,162, 163, 164.”

    From Artificial intelligence-driven multi-omics approaches in Alzheimer's disease: Progress, challenges, and future directions (2025) · cites this paper as [163]

    The Results section (“Differentially vulnerable DA neurons in PD”; page not supplied) identifies a GPNMB-expressing microglial subset associated with a disease-associated microglial marker and a VIM_LHX2 astrocyte subtype expressing reactive markers. It does not establish that these populations perform plaque clearance, neuroinflammation, or synaptic modulation. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Kamath, T., Abdulraouf, A., Burris, S. J., Langlieb, J., Gazestani, V., Nadaf, N. M., Balderrama, K., Vanderburg, C., & Macosko, E. Z.
Affiliations
Broad Institute (US)
Corresponding author
Macosko, Evan Z.
ORCID
Venue
Nature Neuroscience
Publisher
Springer Science and Business Media LLC
Published
2022-05
Volume
25
Issue
5
Pages
588-595
ISSN
  • 1097-6256 (ISSN-L)
  • 1546-1726
DOI
10.1038/s41593-022-01061-1
PMC
PMC9076534
OpenAlex
W4229054631
Cited by
552
References
19
Citations by year
2026: 131 · 2025: 149 · 2024: 142 · 2023: 103 · 2022: 27
FWCI
58.58
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Neuroscience (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (F30AG069446-01, DP2AG058488)
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01MH124602)
Topics
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords
Parkinson's disease, dopaminergic neurons, substantia nigra pars compacta, neuronal vulnerability, single-cell transcriptomics, Slide-seq, angiotensin II type 1 receptor, TP53, NR2F2, neuronal cell types
MeSH terms
Humans, Parkinson Disease, Substantia Nigra, Genomics, Dopaminergic Neurons

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