PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation Article Swipe
Frida Lind‐Holm Mogensen
,
Carole Sousa
,
Corrado Ameli
,
Katja Badanjak
,
Arnaud Muller
,
Tony Kaoma
,
Djalil Coowar
,
Andrea Scafidi
,
Suresh Poovathingal
,
Nathalie Nicot
,
Aurélien Ginolhac
,
Daniela M. Vogt Weisenhorn
,
Wolfgang Wurst
,
Aurélie Poli
,
Petr V. Nazarov
,
Alexander Skupin
,
Anne Grünewald
,
Alessandro Michelucci
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-3931138/v1
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.21203/rs.3.rs-3931138/v1
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-hour 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 hours 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.
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- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.21203/rs.3.rs-3931138/v1
- https://www.researchsquare.com/article/rs-3931138/latest.pdf
- OA Status
- gold
- References
- 67
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4391691014
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4391691014Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.21203/rs.3.rs-3931138/v1Digital Object Identifier
- Title
-
PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammationWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
-
2024Year of publication
- Publication date
-
2024-02-09Full publication date if available
- Authors
-
Frida Lind‐Holm Mogensen, Carole Sousa, Corrado Ameli, Katja Badanjak, Arnaud Muller, Tony Kaoma, Djalil Coowar, Andrea Scafidi, Suresh Poovathingal, Nathalie Nicot, Aurélien Ginolhac, Daniela M. Vogt Weisenhorn, Wolfgang Wurst, Aurélie Poli, Petr V. Nazarov, Alexander Skupin, Anne Grünewald, Alessandro MichelucciList of authors in order
- Landing page
-
https://doi.org/10.21203/rs.3.rs-3931138/v1Publisher landing page
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https://www.researchsquare.com/article/rs-3931138/latest.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
goldOpen access status per OpenAlex
- OA URL
-
https://www.researchsquare.com/article/rs-3931138/latest.pdfDirect OA link when available
- Concepts
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Inflammation, Microglia, Neuroscience, Medicine, Immunology, BiologyTop concepts (fields/topics) attached by OpenAlex
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0Total citation count in OpenAlex
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67Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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