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Loss of Parkinson’s Disease Protein 7 upregulates cytoskeletal protein Palladin and is associated with pregnancy loss

ABSTRACT: Decidualization is a morphological and biochemical reprograming process in preparation for pregnancy. An impaired decidual response can lead to complications like recurrent pregnancy loss (RPL). Parkinson’s disease protein 7 (PARK7), which encodes the protein DJ-1, is renowned for its pivotal role in Parkinson's disease. It manifests a spectrum of physiological functions that hold potential implications for decidualization-related processes. In this study, we elucidate whether DJ-1 can regulate endometrial function. Our findings demonstrate that DJ-1 is expressed in the endometrium of both humans and mice, with increased levels during the time-dependent decidual transformation of human endometrial stromal cells (EnSC) coinciding with the window of implantation. Analysis of human and mice showed that loss of DJ-1 is associated with RPL. Furthermore, knockdown of DJ-1 in decidualized EnSC lead to a reduced in cell proliferation, increase of reactive oxygen species and upregulation of Palladin expression, as quantified through LC/MS. These alterations subsequently contributed to heightened polymerization, augmented cell migration, and increased cellular stiffness. Importantly, these effects were reversed upon DJ-1 overexpression. These findings collectively propose DJ-1 as a crucial regulator of cytoskeleton dynamics and decidual homeostasis, essential for early pregnancy and preventing the onset of RPL.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Ana Velic

LAB HEAD: Madhuri Salker

PROVIDER: PXD051694 | Pride | 2026-01-27

REPOSITORIES: Pride

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			Action	DRS
	20220104_CO_1119MaSa_R37.raw	Raw
	20220104_CO_1119MaSa_R38.raw	Raw
	20220104_CO_1119MaSa_R39.raw	Raw
	20220104_CO_1119MaSa_R40.raw	Raw
	20220104_CO_1119MaSa_R41.raw	Raw

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Project description: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.

Project description: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. In a translational approach, 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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Loss of Parkinson’s Disease Protein 7 upregulates cytoskeletal protein Palladin and is associated with pregnancy loss

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