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Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state

Lookup NU author(s): Dr Christopher Morris, Dr Anne Grunewald



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.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.

Publication metadata

Author(s): Smajic S, Prada-Medina CA, Landoulsi Z, Ghelfi J, Delcambre S, Dietrich C, Jarazo J, Henck J, Balachandran S, Pachchek S, Morris CM, Antony P, Timmermann B, Sauer S, Pereira SL, Schwamborn JC, May P, Grunewald A, Spielmann M

Publication type: Article

Publication status: Published

Journal: Brain

Year: 2022

Volume: 145

Issue: 3

Pages: 964-978

Print publication date: 01/03/2022

Online publication date: 17/12/2021

Acceptance date: 18/11/2021

Date deposited: 20/06/2022

ISSN (print): 0006-8950

ISSN (electronic): 1460-2156

Publisher: Oxford University Press


DOI: 10.1093/brain/awab446

PubMed id: 34919646


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Funder referenceFunder name
Alzheimer’s Research Trust
Alzheimer’s Society
DLR 01GM1925
National Institutes for Health Research Biomedical Research Centre Newcastle
MR/L016451/1Medical Research Council (MRC)
PRIDE17/12244779/ PARK-QC
Parkinson’s UK