title: 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.
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.
authors: Neuroscience Graduate Program, Ajou University School of Medicine, Suwon 442-721, Republic of Korea; National Research Lab of Brain Inflammation, Ajou University School of Medicine, Suwon 442-721, Republic of Korea; Department of Pharmacology, Ajou University School of Medicine, Suwon 442-721, Republic of Korea; Chronic Inflammatory Disease Research Center, Ajou University School of Medicine, Suwon 442-721, Republic of Korea.
authors: Jong-hyeon
authors: JH
authors: Kim
authors: Dong-joo
authors: DJ
authors: Choi
authors: Hey-kyeong
authors: HK
authors: Jeong
authors: Jun
authors: J
authors: Kim
authors: Dae Won
authors: DW
authors: Kim
authors: Soo Young
authors: SY
authors: Choi
authors: Sang-Myun
authors: SM
authors: Park
authors: Young Ho
authors: YH
authors: Suh
authors: Ilo
authors: I
authors: Jou
authors: Eun-Hye
authors: EH
authors: Joe
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000378:metabolism; D001253:Astrocytes / Q000378:metabolism*; D001921:Brain / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism*; D015513:Oncogene Proteins / Q000378:metabolism*; D054464:Peroxiredoxins; D010766:Phosphorylation; D000071617:Protein Deglycase DJ-1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism*
chemical_list: D000893:Anti-Inflammatory Agents; D015513:Oncogene Proteins; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D054464:Peroxiredoxins; C503466:PARK7 protein, mouse; D000071617:Protein Deglycase DJ-1; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; C509248:Ptpn6 protein, mouse
keywords: Brain inflammation; DJ-1; Parkinson's disease; Src-homology 2-domain containing protein tyrosine phosphatase-1