Reference : Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-spe...
Scientific journals : Article
Life sciences : Biochemistry, biophysics & molecular biology
http://hdl.handle.net/10993/49712
Single-cell sequencing of human midbrain reveals glial activation and a Parkinson-specific neuronal state.
English
Smajic, Semra mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Prada-Medina, Cesar A. [> >]
Landoulsi, Zied mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Ghelfi, Jenny mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Delcambre, Sylvie mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Dietrich, Carola [> >]
Jarazo, Javier mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Henck, Jana [> >]
Balachandran, Saranya [> >]
Pachchek, Sinthuja mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Morris, Christopher M. [> >]
Antony, Paul mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience]
Timmermann, Bernd [> >]
Sauer, Sascha [> >]
Pereira, Sandro L. [> >]
Schwamborn, Jens Christian mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology]
May, Patrick mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core]
Grünewald, Anne mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology]
Spielmann, Malte [> >]
2021
Brain : a journal of neurology
Yes (verified by ORBilu)
International
0006-8950
1460-2156
England
[en] Parkinson’s disease ; microglia ; midbrain substantia nigra ; neuroinflammation ; single-cell sequencing
[en] 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.
Researchers ; Professionals ; Students ; General public
http://hdl.handle.net/10993/49712
10.1093/brain/awab446
© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain.
FnR ; FNR9631103 > Anne Grünewald > Model IPD > Modelling Idiopathic Parkinson’S Disease-associated Somatic Variation In Dopaminergic Neurons > 01/01/2016 > 31/12/2022 > 2015

File(s) associated to this reference

Fulltext file(s):

FileCommentaryVersionSizeAccess
Open access
awab446.pdfAuthor preprint2.71 MBView/Open

Bookmark and Share SFX Query

All documents in ORBilu are protected by a user license.