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

Smajić, S., Prada-Medina, C. A., Landoulsi, Z., Ghelfi, J., Delcambre, S., Dietrich, C., et al. (2022). Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain, 145(3), 964-978. doi:10.1093/brain/awab446.

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Smajić, Semra , Author
Prada-Medina, César A.1, Author           
Landoulsi, Zied , Author
Ghelfi, Jenny, Author
Delcambre, Sylvie , Author
Dietrich, Carola1, Author           
Henck, Jana1, Author           
Balachandran, Saranya , Author
Pachchek, Sinthuja , Author
Morris, Christopher M. , Author
Antony, Paul, Author
Timmermann, Bernd2, Author           
Sauer, Sascha, Author
Pereira, Sandro L., Author
Schwamborn, Jens C. , Author
May, Patrick, Author
Grünewald, Anne, Author
Spielmann, Malte1, 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 Core Facility (Head: Bernd Timmermann), Scientific Service (Head: Christoph Krukenkamp), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1479670              

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Free keywords: Parkinson’s disease; microglia; midbrain substantia nigra; neuroinflammation; single-cell sequencing
 Abstract: Idiopathic Parkinson's disease is characterized by a progressive loss of dopaminergic neurons, but the exact disease etiology 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 employing the latest genome-wide association study. We profiled >41 000 single-nuclei transcriptomes of postmortem midbrain from six idiopathic Parkinson's disease patients and five age-/sex-matched controls. To validate our findings in a spatial context, we utilized immunolabeling of the same tissues. Moreover, we analyzed 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 IPD 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 signaling. 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 signaling and immunomodulatory treatments in Parkinson's disease.

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Language(s): eng - English
 Dates: 2021-11-182021-12-172022-03
 Publication Status: Issued
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1093/brain/awab446
PMID: 34919646
 Degree: -

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Title: Brain
  Other : Brain: a journal of neurology
Source Genre: Journal
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Publ. Info: Oxford : Oxford Univ. Press
Pages: - Volume / Issue: 145 (3) Sequence Number: - Start / End Page: 964 - 978 Identifier: ISSN: 0006-8950
CoNE: https://pure.mpg.de/cone/journals/resource/954925385135