Single-cell sequencing of the human midbrain reveals glial activation and a 
neuronal state specific to Parkinson’s disease

Smajić, S.; Prada-Medina, C. A.; Landoulsi​, Z.; Dietrich, C.; Jarazo, J.; Henck, J.; Balachandran, S.; Pachchek, S.; Morris, C. M.; Antony, P.; Timmermann, B.; Sauer, S.; Schwamborn, J. C.; May, P.; Grünewald, A.; Spielmann, M.

doi:10.1101/2020.09.28.20202812

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Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson’s disease

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Dietrich, C.
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Henck, J.
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Timmermann, B.
Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Spielmann, M.
Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society;
Institute of Human Genetics, University of Lübeck, Lübeck, Germany;
Institute of Human Genetics, Kiel University, Kiel, Germany;

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Citation

Smajić, S., Prada-Medina, C. A., Landoulsi, Z., Dietrich, C., Jarazo, J., Henck, J., et al. (2020). Single-cell sequencing of the human midbrain reveals glial activation and a neuronal state specific to Parkinson’s disease. medRxiv, 2020. doi:10.1101/2020.09.28.20202812.

Cite as: https://hdl.handle.net/21.11116/0000-0008-FD66-9

Abstract

Parkinson’s disease (PD) etiology is associated with genetic and environmental factors that lead to a loss ofdopaminergic neurons. However, the functional interpretation of PD-associated risk variants and how othermidbrain cells contribute to this neurodegenerative process are poorly understood. Here, we profiled >41,000single-nuclei transcriptomes of postmortem midbrain tissue from 6 idiopathic PD (IPD) patients and 5matched controls. We show that PD-risk variants are associated with glia- and neuron-specific geneexpression patterns. Furthermore, Microglia and astrocytes presented IPD-specific cell proliferation anddysregulation of genes related to unfolded protein response and cytokine signalling. IPD-microglia revealeda specific pro-inflammatory trajectory. Finally, we discovered a neuronal cell cluster exclusively present inIPD midbrains characterized byCADPS2overexpression and a high proportion of cycling cells. Weconclude that elevated CADPS2 expression is specific to dysfunctional dopaminergic neurons, which havelost their dopaminergic identity and unsuccessful attempt to re-enter the cell cycle.