Objective: We aim to characterize the contribution of each midbrain cell type to PD pathology, and to identify cell types associated with genetic PD-risk variants.

Background: Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons (DaNs) in the substantia nigra, which causes motor and non-motor phenotypes in affected individuals. The molecular changes underlying PD remain largely unknown. So far, the focus of PD research was on DaNs, albeit disease-specific changes can also be observed in non-neuronal cell types of the midbrain.

Method: To characterize each cell type of the midbrain, we applied single-cell sequencing to postmortem tissue. Moreover, to identify PD-relevant midbrain cells, we combined our single-cell transcriptomic data with publically available GWAS data.

Results: We obtained midbrain tissues from five idiopathic PD cases and six matched healthy controls, and sequenced over 41000 single-nuclei transcriptomes. We discovered a PD-specific neuronal cluster characterized by high expression of CADPS2, and low expression of TH. Validation experiments in laser-microdissected postmortem and iPSC-derived DaNs confirmed our results and suggested that the “CADPS2 high” cluster represents dysfunctional DaNs. Additionally, we observed a PD-specific proliferation and gene dysregulations in microglia and astrocytes. Reactive PD astrocytes overexpressed CD44, while PD microglia displayed a pro-inflammatory trajectory defined by increase in IL1B, GPNMB and HSP90AA1. To validate our findings in a spatial context, we deployed IHC and confirmed a nigra-specific increase of microglia in the PD samples. Moreover, microglia were more amoeboid, which is in line with their activated state. We also detected a PD-specific reduction in oligodendrocytes. Interestingly, the remaining idiopathic PD oligodendrocyte cluster showed an overexpression of S100B, indicative of cellular stress. Finally, our GWAS study revealed PD-risk variant enrichments in glial cells and neurons. The most significant enrichment of risk variants was observed in microglia, with the strongest association to LRRK2.

Conclusion: Overall, our single-cell atlas of the idiopathic PD midbrain revealed a disease-specific neuronal state and pan-glial activation. Our findings highlight inflammation as an important aspect of PD pathology that should be explored in more detail in future studies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/single-cell-characterization-of-patient-midbrain-tissue-reveals-tissue-remodeling-and-glial-activation-in-parkinsons-disease/