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

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 +2 more·2013·Neurobiology of Disease

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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Crossref · 10.1016/j.nbd.2013.08.007

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  • DJ-1 may function as a scaffold protein facilitating interaction between STAT1 and SHP-1 that negatively regulates inflammatory responses of microglia.

    “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.”

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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
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 › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Oncology › 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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