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  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., 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.

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Smajić, S. , Author
Prada-Medina, C. A., Author
Landoulsi​, Z., Author
Dietrich, C.1, Author              
Jarazo, J., Author
Henck, J.1, Author              
Balachandran, S., Author
Pachchek, S., Author
Morris, C. M., Author
Antony, P., Author
Timmermann, B.2, Author              
Sauer, S., Author
Schwamborn, J. C., Author
May, P., Author
Grünewald, A., Author
Spielmann, M.1, 3, 4, Author              
Affiliations:
1Human Molecular Genomics (Malte Spielmann), Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_3014183              
2Sequencing (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              
3​Institute of Human Genetics, University of Lübeck, Lübeck, Germany, ou_persistent22              
4Institute of Human Genetics, Kiel University, Kiel, Germany, ou_persistent22              

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 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 by​CADPS2overexpression 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.

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Language(s): eng - English
 Dates: 2020-09-30
 Publication Status: Published online
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 Identifiers: DOI: 10.1101/2020.09.28.20202812
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Title: medRxiv
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