Immunomodulatory role of Parkinson’s disease 7 in inflammatory bowel disease

Abstract

Recently the role of Parkinson’s disease 7 (PARK7) was studied in gastrointestinal diseases, however, the complex role of PARK7 in the intestinal inflammation is still not completely clear. Expression and localization of PARK7 were determined in the colon biopsies of children with inflammatory bowel disease (IBD), in the colon of dextran sodium sulphate (DSS) treated mice and in HT-29 colonic epithelial cells treated with interleukin (IL)-17, hydrogen peroxide (H2O2), tumor necrosis factor (TNF)-α, transforming growth factor (TGF)-β or lipopolysaccharide (LPS). Effect of PARK7 on the synthesis of IBD related cytokines was determined using PARK7 gene silenced HT-29 cells and 3,4,5-trimethoxy-N-(4-(8-methylimidazo(1,2-a)pyridine-2-yl)phenyl)benzamide (Comp23)—compound increasing PARK7 activity—treated mice with DSS-colitis. PARK7 expression was higher in the mucosa of children with Crohn’s disease compared to that of controls. While H2O2 and IL-17 treatment increased, LPS, TNF-α or TGF-β treatment decreased the PARK7 synthesis of HT-29 cells. PARK7 gene silencing influenced the synthesis of IL1B, IL6, TNFA and TGFB1 in vitro. Comp23 treatment attenuated the ex vivo permeability of colonic sacs, the clinical symptoms, and mucosal expression of Tgfb1, Il1b, Il6 and Il10 of DSS-treated mice. Our study revealed the role of PARK7 in the regulation of IBD-related inflammation in vitro and in vivo, suggesting its importance as a future therapeutic target.

Mechanistic Insights Into Gut Microbiome Dysbiosis-Mediated Neuroimmune Dysregulation and Protein Misfolding and Clearance in the Pathogenesis of Chronic Neurodegenerative Disorders

“…Similarly, an autosomal recessive gene associated with early Parkinsonism, DJ-1 (PARK 7), is dysfunctional in human colonic tissue samples as well as in in vitro and in vivo experimental models of colitis (Zhang et al, 2020). As both IBD and PD have compromised intestinal barrier functions, DJ-1 deficiency promotes cytokinemediated inflammation (IL-1β, IL-6, TNFα, and TGFB1) and apoptosis of intestinal epithelial cells via a p53-dependent mechanism in vitro, in ex vivo colonic sacs, and in vivo (van IJzendoorn and Derkinderen, 2019; Zhang et al, 2020;Lippai et al, 2021). This further supports the hypothesis that the onset, progression and severity of IBD and PD are aggravated by geneenvironment interactions occurring at both the host and gut microbiome levels.…”

PARK7/DJ-1 as a Therapeutic Target in Gut-Brain Axis Diseases

“…The role of MMP-3 was also suggested in the proteomic cleavage and degradation of PARK7/DJ-1 in CATH neuronal cells [ 93 ]. Our very recent results showed that inflammatory mediators of IBD, including LPS, TNF-α, and TGF-β, decreased the expression of PARK7/DJ-1 in HT-29 colonic adenocarcinoma cells [ 11 ].…”

“…The role of cellular homeostasis regulator cell cycle autoantigen (SG2NA) has also been demonstrated to increase the expression of PARK7/DJ-1 by inhibiting its proteasome-mediated degradation in Neuro2a neuroblastoma cells [ 98 , 99 , 100 ]. Finally, our recent study showed that IL-17 and hydrogen peroxide increases the expression of PARK7/DJ-1 [ 11 ]. Interestingly, while increased oxidative stress is one of the main mediators of proteomic degradation of PARK7/DJ-1, our results showed that as a positive feedback mechanism it can facilitate its synthesis [ 11 ].…”

“…Finally, our recent study showed that IL-17 and hydrogen peroxide increases the expression of PARK7/DJ-1 [ 11 ]. Interestingly, while increased oxidative stress is one of the main mediators of proteomic degradation of PARK7/DJ-1, our results showed that as a positive feedback mechanism it can facilitate its synthesis [ 11 ].…”

“…Our and other studies have demonstrated that intestinal expression of PARK7/DJ-1 is altered in the mucosa of patients with celiac disease or IBD [ 10 ]. Furthermore, experimental results revealed that PARK7/DJ-1 affects intestinal inflammation and protects the integrity of the mucosal epithelial barrier as well [ 11 , 12 , 13 ]. In a recent study, Singh et al demonstrated that genetic deletion of PARK7/DJ-1 leads to dysbiosis and increased expression of pro-inflammatory molecules in the intestine, and also that of PD-related genes in the midbrain of mice [ 14 ].…”