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Smajić S, Prada-Medina CA, Landoulsi Z, et al. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain. 2021;doi: 10.1093/brain/awab446.
Smajić, S., Prada-Medina, C. A., Landoulsi, Z., Ghelfi, J., Delcambre, S., Dietrich, C., Jarazo, J., Henck, J., Balachandran, S., Pachchek, S., Morris, C. M., Antony, P., Timmermann, B., Sauer, S., Pereira, S. L., Schwamborn, J. C., May, P., Grünewald, A., & Spielmann, M. (2021). Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain : a journal of neurology, . https://doi.org/10.1093/brain/awab446
Smajić, Semra, et al. "Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state." Brain : a journal of neurology vol. (2021). doi: https://doi.org/10.1093/brain/awab446
Smajić 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, Grünewald A, Spielmann M. Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state. Brain. 2021 Dec 17; doi: 10.1093/brain/awab446. Epub 2021 Dec 17. PMID: 34919646.
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Brain. 2021 Dec 17; doi: 10.1093/brain/awab446. Epub 2021 Dec 17.

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

Brain : a journal of neurology

Semra Smajić, Cesar A Prada-Medina, Zied Landoulsi, Jenny Ghelfi, Sylvie Delcambre, Carola Dietrich, Javier Jarazo, Jana Henck, Saranya Balachandran, Sinthuja Pachchek, Christopher M Morris, Paul Antony, Bernd Timmermann, Sascha Sauer, Sandro L Pereira, Jens C Schwamborn, Patrick May, Anne Grünewald, Malte Spielmann

Affiliations

  1. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362 Esch-sur-Alzette, Luxembourg.
  2. Max Planck Institute for Molecular Genetics, D-14195 Berlin, Germany.
  3. OrganoTherapeutics SARL-S, L-4362 Esch-sur-Alzette, Luxembourg.
  4. Institute of Human Genetics, Kiel University, D-42118 Kiel, Germany.
  5. Newcastle Brain Tissue Resource, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, NE1 7RU Newcastle upon Tyne, UK.
  6. Max-Delbrück-Centrum für Molekulare Medizin, Genomics Group, D-13125 Berlin, Germany.
  7. Institute of Neurogenetics, University of Lübeck, D-23562 Lübeck, Germany.
  8. Institute of Human Genetics, University of Lübeck, D-23562 Lübeck, Germany.

PMID: 34919646 DOI: 10.1093/brain/awab446

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.

© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.

Keywords: Parkinson’s disease; microglia; midbrain substantia nigra; neuroinflammation; single-cell sequencing

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