Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state
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Abstract
Idiopathic Parkinson’s disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease aetiology remains largely unknown. To date, Parkinson’s disease research has mainly focused on nigral dopaminergic neurons, although recent studies suggest disease-related changes also in non-neuronal cells and in midbrain regions beyond the substantia nigra. While there is some evidence for glial involvement in Parkinson’s disease, the molecular mechanisms remain poorly understood. The aim of this study was to characterize the contribution of all cell types of the midbrain to Parkinson’s disease pathology by single-nuclei RNA sequencing and to assess the cell type-specific risk for Parkinson’s disease using the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of post-mortem midbrain from six idiopathic Parkinson’s disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabelling of the same tissues. Moreover, we analysed Parkinson’s disease-associated risk enrichment in genes with cell type-specific expression patterns. We discovered a neuronal cell cluster characterized by CADPS2 overexpression and low TH levels, which was exclusively present in idiopathic Parkinson’s disease midbrains. Validation analyses in laser-microdissected neurons suggest that this cluster represents dysfunctional dopaminergic neurons. With regard to glial cells, we observed an increase in nigral microglia in Parkinson’s disease patients. Moreover, nigral idiopathic Parkinson’s disease microglia were more amoeboid, indicating an activated state. We also discovered a reduction in idiopathic Parkinson’s disease oligodendrocyte numbers with the remaining cells being characterized by a stress-induced upregulation of S100B. Parkinson’s disease risk variants were associated with glia- and neuron-specific gene expression patterns in idiopathic Parkinson’s disease cases. Furthermore, astrocytes and microglia presented idiopathic Parkinson’s disease-specific cell proliferation and dysregulation of genes related to unfolded protein response and cytokine signalling. While reactive patient astrocytes showed CD44 overexpression, idiopathic Parkinson’s disease microglia revealed a pro-inflammatory trajectory characterized by elevated levels of IL1B, GPNMB and HSP90AA1. Taken together, we generated the first single-nuclei RNA sequencing dataset from the idiopathic Parkinson’s disease midbrain, which highlights a disease-specific neuronal cell cluster as well as ‘pan-glial’ activation as a central mechanism in the pathology of the movement disorder. This finding warrants further research into inflammatory signalling and immunomodulatory treatments in Parkinson’s disease.
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Astrocytes within the substantia nigra pars compacta can become reactive in Parkinson's disease.
“can also become reactive in PD”
From Mitochondrial DNA Damage in Substantia Nigra Pars Compacta Astrocytes Exacerbates Dopaminergic Neuron Loss in a 6-Hydroxydopamine Mouse Model of Parkinsonism (2026) · cites this paper as Smajic et al. 2022
The Results report that idiopathic Parkinson’s disease astrocytes were enriched at the reactive end of an astrogliosis trajectory, and the Discussion describes reactive astrogliosis in patient cells. The evidence concerns midbrain astrocytes; the passages do not localize that finding specifically to the substantia nigra pars compacta. (LLM, conf=0.84)
Experimental — accuracy not yet measuredPostmortem analysis of ventral midbrains from PD patients revealed a significantly increased number of microglia with an ameboid shape, suggestive of an activated state.
“Postmortem analysis of ventral midbrains from PD patients revealed a significantly increased number of microglia with an ameboid shape, suggestive of an activated state.86”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [86]
Studies have identified a significant association between PD risk variants and microglia.
“Importantly, studies have identified a significant association between PD risk variants and microglia.86,87”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [86]
Neuroinflammation and microglial activation are consistent features across neurodegenerative diseases, including AD, PD, HD, FTD, and ALS.
“Indeed, neuroinflammation and microglial activation are consistent features across neurodegenerative diseases, including AD,126–128 PD,86,129 HD,130,131 FTD,91,132 and ALS.89,133–135”
From Microbiota–gut–brain axis and its therapeutic applications in neurodegenerative diseases (2024) · cites this paper as [86]
In postmortem midbrain samples, PD patients have an increased number of reactive microglia and a reduction in oligodendrocyte numbers compared to controls.
“the researchers observed an increased number in reactive microglia and a reduction in oligodendrocyte numbers in PD patients.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [215]
Through snRNA-seq of frozen midbrain tissue from PD patients and controls, seven distinct microglia subpopulations were identified based on expression of specific marker genes.
“Through snRNA-seq analysis of frozen midbrain tissue from PD patients and controls, seven distinct microglia subpopulations were identified based on the expression of specific marker genes.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [215]
Microglia in the SN of PD patients show a higher proportion of amoeboid morphology, indicative of a reactive state.
“Microglia in the SN of PD patients showed a higher proportion of amoeboid morphology, which is indicative of a reactive state.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [215]
Reactive microglia states in PD are enriched in cytokine secretion and the stress response to unfolded protein pathways.
“The study also revealed that the reactive microglia states are enriched in cytokine secretion and the stress response to unfolded protein pathways.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [215]
The microglial activation trajectory extends from P2RY12high cells to two activation branches, one with highly expressed HSP90AA1 or IL1B and the other containing GPNMBhigh cells.
“The microglial activation trajectory extends from P2RY12high cells to two activation branches, one with highly expressed HSP90AA1 or IL1B241 cells and the other containing GPNMBhigh cells.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [215]
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Regulatory system for the G1‐arrest during neuronal development in Drosophila
Tsuda, L., & Lim, Y. (2014) · Development Growth & Differentiation · doi:10.1111/dgd.12130 · Cited by 7 · see citing works
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Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets
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Martins-Ferreira, R., Calafell-Segura, J., Leal, B., Rodríguez-Ubreva, J., Martínez-Saez, E., Mereu, E., Pinho E Costa, P., Laguna, A., & Ballestar, E. (2025) · Nature Communications · doi:10.1038/s41467-025-56124-1 · Cited by 123 · see citing works
Axonal energy metabolism, and the effects in aging and neurodegenerative diseases
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Ayala, D. A., Hall, G. M., Das, D., Tijerina, E., Villagran, L. L., Khan, Z., Paliwal, D., Anand, A., Rimer, M., & Srinivasan, R. (2026) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-026-01713-x · Cited by 1 · see citing works
- Authors
- Smajić, S., Prada-Medina, C. A., Landoulsi, Z., Ghelfi, J., Delcambre, S., Dietrich, C., Jarazo, J., Henck, J., Balachandran, S., Pachchek, S., Morris, C. M., Antony, P., Timmermann, B., Sauer, S., Pereira, S. L., Schwamborn, J. C., May, P., Grünewald, A., & Spielmann, M.
- Affiliations
- University of Luxembourg (LU)
- Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany
- Max Planck Institute for Molecular Genetics (DE)
- Christian-Albrechts-Universität zu Kiel (DE)
- Newcastle University (GB)
- Max Delbrück Center (DE)
- Corresponding author
- Grünewald, Anne
- Spielmann, Malte
- ORCID
- Venue
- Brain
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-12-17
- Volume
- 145
- Issue
- 3
- Pages
- 964-978
- ISSN
- 0006-8950 (ISSN-L)
- 1460-2156
- PMC
- PMC9050543
- OpenAlex
- W4200349851
- Cited by
- 590
- References
- 80
- Citations by year
- 2026: 148 · 2025: 147 · 2024: 150 · 2023: 96 · 2022: 43 · 2021: 4 · 2012: 1
- FWCI
- 38.40
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Brain (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (acceptedVersion)
- Open Repository and Bibliography (University of Luxembourg) (submittedVersion, other-oa)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Luxembourg National Research Fund (PRIDE17/12244779/PARK-QC)
- Le Foyer Assurances Luxembourg
- National Centre of Excellence in Research on Parkinson’s disease
- ‘MiRisk-Parkinson’s disease’ (C17/BM/11676395)
- ‘ProtectMove’ (INTER/DFG/19/14429377)
- Deutsche Forschungsgemeinschaft (SP1532/3-1, SP1532/4-1, SP1532/5-1)
- Deutsches Zentrum für Luft- und Raumfahrt
- Newcastle Brain Tissue Resource from UK MRC (MR/L016451/1)
- National Institutes for Health Research Biomedical Research Centre Newcastle
- Parkinson’s UK (258197, SC037554)
- Topics
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Keywords
- Parkinson's disease, midbrain, single-nucleus RNA sequencing, glial activation, microglia, oligodendrocytes, astrocytes, dopaminergic neurons, Th, S100B, unfolded protein response, cytokine signaling, IL1B, GPNMB, HSP90AA1, CD44
- MeSH terms
- Humans, Membrane Glycoproteins, Mesencephalon, Parkinson Disease, Substantia Nigra, Microglia, Genome-Wide Association Study, Dopaminergic Neurons
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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