Cited by 107Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsCytokine Signaling Pathways and Interactions

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DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1

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Kim, Jong-hyeon, Choi, Dong-joo, Jeong, Hey-kyeong, Kim, Jun, Kim, Dae Won, Choi, Soo Young, Park, Sang-Myun, Suh, Young Ho, Jou, Ilo, Joe, Eun-Hye·2013·Neurobiology of Disease

DOI 10.1016/j.nbd.2013.08.007

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Abstract

Parkinson's disease (PD) is a progressive neurodegenerative movement disorder caused by the death of dopaminergic neurons in the substantia nigra. Importantly, altered astrocyte and microglial functions could contribute to neuronal death in PD. In this study, we demonstrate a novel mechanism by which DJ-1 (PARK7), an early onset autosomal-recessive PD gene, negatively regulates inflammatory responses of astrocytes and microglia by facilitating the interaction between STAT1 and its phosphatase, SHP-1 (Src-homology 2-domain containing protein tyrosine phosphatase-1). Astrocytes and microglia cultured from DJ-1-knockout (KO) mice exhibited increased expression of inflammatory mediators and phosphorylation levels of STAT1 (p-STAT1) in response to interferon-gamma (IFN-γ) compared to cells from wild-type (WT) mice. DJ-1 deficiency also attenuated IFN-γ-induced interactions of SHP-1 with p-STAT1 and STAT1, measured 1 and 12h after IFN-γ treatment, respectively. Subsequent experiments showed that DJ-1 directly interacts with SHP-1, p-STAT1, and STAT1. Notably, DJ-1 bound to SHP-1 independently of IFN-γ, whereas the interactions of DJ-1 with p-STAT1 and STAT1 were dependent on IFN-γ. Similar results were obtained in brain slice cultures, where IFN-γ induced much stronger STAT1 phosphorylation and inflammatory responses in KO slices than in WT slices. Moreover, IFN-γ treatment induced neuronal damage in KO slices. Collectively, these findings suggest that DJ-1 may function as a scaffold protein that facilitates SHP-1 interactions with p-STAT1 and STAT1, thereby preventing extensive and prolonged STAT1 activation. Thus, the loss of DJ-1 function may increase the risk of PD by enhancing brain inflammation.

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Additional file 9 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750090
Additional file 11 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750096
Additional file 2 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750069
Additional file 10 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750093
Additional file 6 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750081
Additional file 5 of PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation
Lind-Holm Mogensen, F., Sousa, C., Ameli, C., Badanjak, K., Pereira, S. L., Muller, A., Kaoma, T., Coowar, D., Scafidi, A., Poovathingal, S. K., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26750078
Additional file 1 of Mapping dynamic molecular changes in hippocampal subregions after traumatic brain injury through spatial proteomics
Maity, S., Huang, Y., Kilgore, M. D., Thurmon, A. N., Vaasjo, L. O., Galazo, M. J., Xu, X., Cao, J., Wang, X., Ning, B., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26719560

Authors: Kim, J.-H., Choi, D.-J., Jeong, H.-K., Kim, J., Kim, D. W., Choi, S. Y., Park, S.-M., Suh, Y. H., Jou, I., & Joe, E.-H.
Affiliations: Ajou University (KR)
Hallym University (KR)
Corresponding author: Joe, Eun-Hye
ORCID: Choi, Dong-joo
Kim, Dae Won
Choi, Soo Young
Suh, Young Ho
Jou, Ilo
Joe, Eun-Hye
Venue: Neurobiology of Disease
Publisher: Elsevier BV
Published: 2013-12
Volume: 60
Pages: 1-10
ISSN: 0969-9961 (ISSN-L)
DOI: 10.1016/j.nbd.2013.08.007
OpenAlex: W1983688655
Cited by: 102
References: 63
Citations by year: 2026: 3 · 2025: 7 · 2024: 17 · 2023: 5 · 2022: 6 · 2021: 8 · 2020: 10 · 2019: 6 · 2018: 8 · 2017: 9 · 2016: 9 · 2015: 9 · 2014: 4
FWCI: 4.11
Type: journal article
Language: en
Open access: green
doaj.org
Licence: cc-by-sa
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations: Neurobiology of Disease (publishedVersion)
PubMed (publishedVersion)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
AJOU Open Repository (Ajou University) (submittedVersion)
Funders: Korean government (MEST) (2-2008025-0)
KOSEF (NRF-2012R1A5A2051429)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Clinical Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Immunology and Microbiology › Immunology › Cytokine Signaling Pathways and Interactions
Keywords: DJ-1, STAT1, SHP-1, protein tyrosine phosphatase, STAT1 phosphorylation, interferon-gamma, microglia, astrocytes, neuroinflammation, Parkinson's disease, neuronal injury, scaffold proteins, protein-protein interaction
MeSH terms: Protein Deglycase DJ-1, Animals, Anti-Inflammatory Agents, Astrocytes, Brain, Interferon-gamma, Phosphorylation, Oncogene Proteins, Microglia, Mice, Knockout, STAT1 Transcription Factor, Mice, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Peroxiredoxins

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DJ-1 facilitates the interaction between STAT1 and its phosphatase, SHP-1, in brain microglia and astrocytes: A novel anti-inflammatory function of DJ-1

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