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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
Open accessAbstract
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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“Additionally, DJ-1 may function as a scaffold protein facilitating the interaction between signal-transducers and activators of transcription (STAT1) and its phosphatase, Src-homology 2-domain containing protein tyrosine phosphatase-1 (SHP-1) that negatively regulates inflammatory responses of microglia.”
From Microglia in neurodegenerative diseases: mechanism and potential therapeutic targets (2023) · cites this paper as [264]
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Metadata
- 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
- Venue
- Neurobiology of Disease
- Publisher
- Elsevier BV
- Published
- 2013-12
- Volume
- 60
- Pages
- 1-10
- ISSN
- 0969-9961 (ISSN-L)
- 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
- 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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