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

Abstract

It is increasingly known that Parkinson's (PD) and Alzheimer's (AD) diseases occur more frequently in patients with inflammatory gastrointestinal diseases including inflammatory bowel (IBD) or celiac disease, indicating a pathological link between them. Although epidemiological observations suggest the existence of the gut-brain axis (GBA) involving systemic inflammatory and neural pathways, little is known about the exact molecular mechanisms. Parkinson's disease 7 (PARK7/DJ-1) is a multifunctional protein whose protective role has been widely demonstrated in neurodegenerative diseases, including PD, AD, or ischemic stroke. Recent studies also revealed the importance of PARK7/DJ-1 in the maintenance of the gut microbiome and also in the regulation of intestinal inflammation. All these findings suggest that PARK7/DJ-1 may be a link and also a potential therapeutic target in gut and brain diseases. In this review, therefore, we discuss our current knowledge about PARK7/DJ-1 in the context of GBA diseases.

Keywords: Alzheimer’s disease; Crohn’s disease; PARK7/DJ-1; Parkinson’s disease; blood-brain barrier; gut-brain axis; inflammatory bowel diseases; neurodegenerative disorders; oxidative stress; ulcerative colitis.

Figure 1

The role of intestinal alterations in the development of systemic inflammation. Disturbance of the gut microbiome leads to impairment of the epithelial barrier integrity and penetration of the luminal bacteria into the mucosal layer, thereby activating the resident immune cells. In the injured intestine the inflammatory factors, bacteria, and their parts can enter the circulation extending the intestinal inflammation to systemic inflammation.

Figure 2

Effect of PARK7/DJ-1 on the formation of AGEs. AGE formation is facilitated by reactive GDPs. AGEs activate their AGE receptors leading to oxidative stress and inflammation. To eliminate toxic GDPs, the glutathione system degrades them to nontoxic lactate. PARK7/DJ-1 is involved in this process at several points. Indeed, PARK7/DJ-1 has its own glyoxalase activity, and upregulates the glyoxalase-1 and 2 enzyme activity, which is responsible for the elimination of GDPs. In addition, PARK7/DJ-1 has deglycase activity, thereby preventing the glycation of macromolecules and AGE formation. Finally, as an antioxidant, PARK7/DJ-1 protects the cells against the harmful effect of oxidative stress.

Figure 3

Role of PARK7/DJ-1 against oxidative damage of duodenal epithelial cells in celiac disease. Our study demonstrated that PARK7/DJ-1-binding Comp23 altered the expression of stress-response elements, including antioxidant and cell-cycle regulator genes, and normalized the expression and localization of CAMs, contributing to the maintenance of mucosal integrity as demonstrated by our ex vivo experiment.

Figure 4

Effect of PARK7/DJ-1 on DSS treatment-induced colitis. Comp23 treatment decreased the mucosal expression of IL-1β, IL-6, IL-10, and TGF-β in DSS-treated mice. Similarly, following DSS treatment, decreased body weight, a higher disease activity index, and increased expression of TNF-α, IL-1β, IL-6, IL-8, MCP-1, and CCL3 were observed in the colon of DSS treated PARK7/DJ-1 KO compared to that of WT mice.

Figure 5

Effect of inflammatory factors on the synthesis of PARK7/DJ-1 and that of gene silencing of PARK7/DJ-1 on the synthesis of different inflammatory factors. IL-17 and H₂O₂ treatment decrease while TNF-α, TGF-β, and LPS treatment increases the expression of PARK7/DJ-1 in HT-29 colonic epithelial cells. PARK7/DJ-1 RNA silencing facilitates TNF-α and IL-8 expression and decreases IL-1β and IL-6 expression in HT-29 or Caco2 colon epithelial cells.

Figure 6

The role of PARK7/DJ-1 on immune cell activation in DSS-induced colitis. Symptoms of DSS-induced colitis were milder, and the expression of inflammatory cytokines was lower in the colon of KO to WT chimeric mice compared with WT to WT mice. Nevertheless, symptoms of DSS-induced colitis were more severe, and the expression of inflammatory cytokines was higher in the colon of WT to KO chimeric mice compared with KO to KO mice.

Figure 7

The role of PARK7/DJ-1 in GBA diseases. PARK7/DJ-1, through its antioxidant, anti-inflammatory, glyoxalase, and chaperon activity properties, plays a role in the maintenance of intestinal integrity, thus diminishing the local and the systemic inflammation. The systemic inflammation of intestinal origin can be considered as a possible factor that negatively regulates PARK7/DJ-1 in the brain. Similarly to the gut, PARK7/DJ-1 also plays a protective role in the brain, therefore, its negative regulation enhances pathological GBA crosstalk and the development of neurodegenerative diseases.