Article (Scientific journals)
iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.
BADANJAK, Katja; MULICA, Patrycja; SMAJIC, Semra et al.
2021In Frontiers in Cell and Developmental Biology, 9, p. 740758
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Keywords :
disease modeling; iPSC; idiopathic Parkinson’s disease; microglia; neuroinflammation
Abstract :
[en] Parkinson's disease (PD) is a neurodegenerative disease with unknown cause in the majority of patients, who are therefore considered "idiopathic" (IPD). PD predominantly affects dopaminergic neurons in the substantia nigra pars compacta (SNpc), yet the pathology is not limited to this cell type. Advancing age is considered the main risk factor for the development of IPD and greatly influences the function of microglia, the immune cells of the brain. With increasing age, microglia become dysfunctional and release pro-inflammatory factors into the extracellular space, which promote neuronal cell death. Accordingly, neuroinflammation has also been described as a feature of PD. So far, studies exploring inflammatory pathways in IPD patient samples have primarily focused on blood-derived immune cells or brain sections, but rarely investigated patient microglia in vitro. Accordingly, we decided to explore the contribution of microglia to IPD in a comparative manner using, both, iPSC-derived cultures and postmortem tissue. Our meta-analysis of published RNAseq datasets indicated an upregulation of IL10 and IL1B in nigral tissue from IPD patients. We observed increased expression levels of these cytokines in microglia compared to neurons using our single-cell midbrain atlas. Moreover, IL10 and IL1B were upregulated in IPD compared to control microglia. Next, to validate these findings in vitro, we generated IPD patient microglia from iPSCs using an established differentiation protocol. IPD microglia were more readily primed as indicated by elevated IL1B and IL10 gene expression and higher mRNA and protein levels of NLRP3 after LPS treatment. In addition, IPD microglia had higher phagocytic capacity under basal conditions-a phenotype that was further exacerbated upon stimulation with LPS, suggesting an aberrant microglial function. Our results demonstrate the significance of microglia as the key player in the neuroinflammation process in IPD. While our study highlights the importance of microglia-mediated inflammatory signaling in IPD, further investigations will be needed to explore particular disease mechanisms in these cells.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
BADANJAK, Katja ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
MULICA, Patrycja ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
SMAJIC, Semra ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
DELCAMBRE, Sylvie ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
TRANCHEVENT, Leon-Charles ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Diederich, Nico
Rauen, Thomas
SCHWAMBORN, Jens Christian ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Developmental and Cellular Biology
GLAAB, Enrico  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Biomedical Data Science
Cowley, Sally A.
ANTONY, Paul ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience
Pereira, Sandro L.
Venegas, Carmen
GRÜNEWALD, Anne  ;  University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
More authors (4 more) Less
External co-authors :
yes
Language :
English
Title :
iPSC-Derived Microglia as a Model to Study Inflammation in Idiopathic Parkinson's Disease.
Publication date :
2021
Journal title :
Frontiers in Cell and Developmental Biology
ISSN :
2296-634X
Publisher :
Frontiers, Lausanne, Switzerland
Volume :
9
Pages :
740758
Peer reviewed :
Peer Reviewed verified by ORBi
FnR Project :
FNR9631103 - Modelling Idiopathic Parkinson'S Disease-associated Somatic Variation In Dopaminergic Neurons, 2015 (01/01/2016-31/12/2022) - Anne Grünewald
Commentary :
Copyright © 2021 Badanjak, Mulica, Smajic, Delcambre, Tranchevent, Diederich, Rauen, Schwamborn, Glaab, Cowley, Antony, Pereira, Venegas and Grünewald.
Available on ORBilu :
since 07 January 2022

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