[en] [en] BACKGROUND: Specific microglia responses are thought to contribute to the development and progression of neurodegenerative diseases, including Parkinson's disease (PD). However, the phenotypic acquisition of microglial cells and their role during the underlying neuroinflammatory processes remain largely elusive. Here, according to the multiple-hit hypothesis, which stipulates that PD etiology is determined by a combination of genetics and various environmental risk factors, we investigate microglial transcriptional programs and morphological adaptations under PARK7/DJ-1 deficiency, a genetic cause of PD, during lipopolysaccharide (LPS)-induced inflammation.
METHODS: Using a combination of single-cell RNA-sequencing, bulk RNA-sequencing, multicolor flow cytometry and immunofluorescence analyses, we comprehensively compared microglial cell phenotypic characteristics in PARK7/DJ-1 knock-out (KO) with wildtype littermate mice following 6- or 24-h intraperitoneal injection with LPS. For translational perspectives, we conducted corresponding analyses in human PARK7/DJ-1 mutant induced pluripotent stem cell (iPSC)-derived microglia and murine bone marrow-derived macrophages (BMDMs).
RESULTS: By excluding the contribution of other immune brain resident and peripheral cells, we show that microglia acutely isolated from PARK7/DJ-1 KO mice display a distinct phenotype, specially related to type II interferon and DNA damage response signaling, when compared with wildtype microglia, in response to LPS. We also detected discrete signatures in human PARK7/DJ-1 mutant iPSC-derived microglia and BMDMs from PARK7/DJ-1 KO mice. These specific transcriptional signatures were reflected at the morphological level, with microglia in LPS-treated PARK7/DJ-1 KO mice showing a less amoeboid cell shape compared to wildtype mice, both at 6 and 24 h after acute inflammation, as also observed in BMDMs.
CONCLUSIONS: Taken together, our results show that, under inflammatory conditions, PARK7/DJ-1 deficiency skews microglia towards a distinct phenotype characterized by downregulation of genes involved in type II interferon signaling and a less prominent amoeboid morphology compared to wildtype microglia. These findings suggest that the underlying oxidative stress associated with the lack of PARK7/DJ-1 affects microglia neuroinflammatory responses, which may play a causative role in PD onset and progression.
Research center :
ULHPC - University of Luxembourg: High Performance Computing
Sousa, Carole; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, 6A, rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg ; International Iberian Nanotechnology Laboratory, 4715-330, Braga, Portugal
AMELI, Corrado ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Integrative Cell Signalling > Team Alexander SKUPIN
BADANJAK, Katja ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > FSTM Faculty administration > Research Facilitators
Pereira, Sandro L; Molecular and Functional Neurobiology Group, Luxembourg Centre for Systems Biomedicine, University of Luxembourg, L-4362, Esch-sur-Alzette, Luxembourg
Muller, Arnaud; Bioinformatics Platform, Department of Medical Informatics, Luxembourg Institute of Health, L-1445, Strassen, Luxembourg ; LuxGen Genome Center, Luxembourg Institute of Health and Laboratoire National de Santé, L-3555, Dudelange, Luxembourg
Kaoma, Tony; Bioinformatics Platform, Department of Medical Informatics, Luxembourg Institute of Health, L-1445, Strassen, Luxembourg
COOWAR, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Rodent facility
Scafidi, Andrea; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, 6A, rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg ; Faculty of Science, Technology and Medicine, University of Luxembourg, L-4365, Esch-sur-Alzette, Luxembourg
POOVATHINGAL, Suresh Kumar ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine > Integrative Cell Signalling
TZIORTZIOU, Maria ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
ANTONY, Paul ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services > Imaging Platform
Nicot, Nathalie; LuxGen Genome Center, Luxembourg Institute of Health and Laboratoire National de Santé, L-3555, Dudelange, Luxembourg
GINOLHAC, Aurélien ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Vogt Weisenhorn, Daniela M; Institute of Developmental Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany ; Technische Universität München-Weihenstephan, 85354, Freising, Germany
Wurst, Wolfgang; Institute of Developmental Genetics, Helmholtz Zentrum München-German Research Center for Environmental Health, 85764, Neuherberg, Germany ; Technische Universität München-Weihenstephan, 85354, Freising, Germany ; German Center for Neurodegenerative Diseases (DZNE), 81377, Munich, Germany ; Munich Cluster for Systems Neurology (SyNergy), 81377, Munich, Germany ; Deutsche Zentrum für Psychische Gesundheit (DZPG), 80336, Munich, Germany
Poli, Aurélie; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, 6A, rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg
Nazarov, Petr V; Bioinformatics Platform, Department of Medical Informatics, Luxembourg Institute of Health, L-1445, Strassen, Luxembourg ; Multiomics Data Science Group, Department of Cancer Research, Luxembourg Institute of Health, L-1445, Strassen, Luxembourg
SKUPIN, Alexander ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Integrative Cell Signalling ; Department of Neuroscience, University of California San Diego, La Jolla, CA, 92093, USA
GRÜNEWALD, Anne ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Molecular and Functional Neurobiology
Michelucci, Alessandro; Neuro-Immunology Group, Department of Cancer Research, Luxembourg Institute of Health, 6A, rue Nicolas-Ernest Barblé, L-1210, Luxembourg, Luxembourg. alessandro.michelucci@lih.lu
F.L-HM. was supported by the Luxembourg National Research Fund (FNR) through the FNR-PRIDE program i2TRON for doctoral education (PRIDE/14254520/I2TRON). C.S. was supported by the FNR (AFR/6916713) and the Fondation du P\u00E9lican de Mie et Pierre Hippert-Faber under the aegis of Fondation de Luxembourg. C.A. and K.B. were supported by the FNR-PRIDE program CriTiCS for doctoral education (PRIDE/10907093/CriTiCS). In addition, C.A. was supported by the CMCM (Caisse M\u00E9dico-Compl\u00E9mentaire Mutualiste Luxembourg) matching grant. MT received funding from the FNR as part of the FNR-PRIDE program NextImmune2 for doctoral education (PRIDE21/16749720). W.W. was supported by the Deutsche Zentrum f\u00FCr Psychische Gesundheit (DZPG), site Munich-Augsburg. PVN was supported by a FNR CORE grant (C21/BM/15739125/DIOMEDES). Al.S. was supported by the FNR through an INTER grant (INTER/DFG/17/11583046). AG was supported by the FNR within the framework of the ATTRACT (Model-IPD, FNR9631103) program as well as the National Centre of Excellence in Research on Parkinson\u2019s disease (NCER-PD, FNR/NCER13/BM/11264123). In addition, AG and SLP received funding from the FNR within the framework of a CORE grant (\u201CCAMeSyn\u201D, C19/BM/13688526). Lastly, we acknowledge financial support from the Action LIONS \u00AB Vaincre le Cancer\u00BB Luxembourg. For the purpose of open access, and in fulfilment of the obligations arising from the FNR grant agreement, the author has applied a Creative Commons Attribution 4.0 International (CC BY 4.0) license to any Author Accepted Manuscript version arising from this submission.We are grateful to Ms. Amandine Bernard for mouse genotyping and, together with Mr. Alexandros Pailas, for technical support with Western blotting as well as to Ms. Virginie Baus for helping with the cryostat tissue cutting. We would also like to thank Dr Eduardo Rosales Jubal for advices on statistical analyses of qPCR and MIC-MAC results. Part of the analyses were carried out using the High Performance Computing (HPC) facilities of the University of Luxembourg (https://hpc.uni.lu).
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