Mild Chronic Colitis Exacerbates Intracerebral Inflammation in Mice with Parkinson's Disease Through LRRK2-Mediated Regulation of NF-κB Activation and Inhibition of Nrf2.

Background and Objective: Inflammatory bowel disease (IBD) is a known risk factor for Parkinson's disease (PD). Leucine-rich repeat kinase 2 (LRRK2), a protein associated with both disease, regulates inflammation in the colon and brain. However, the precise mechanism by which LRRK2 mediates the crosstalk between intestinal inflammation and PD neuropathology remains unclear. This study aims to elucidate how LRRK2 mediates the inflammatory response in both the gut and brain. Methods: A dual-hit (DSS+MPTP) mouse model was established to induce IBD and PD, along with separate single DSS-induced colitis and MPTP-induced PD models. LRRK2 expression was analyzed in the colon and striatum. Intestinal barrier integrity (ZO-1, Occludin), dopaminergic neuron loss and inflammation (TH, Iba-1 staining in SNpc/striatum), NF-κB and Nrf2 pathways activity, and levels of inflammatory cytokines (TNF-α, IL1-β, IL-6 and IL-10) in the colon and striatum was assessed. Results: In the colon, LRRK2 expression was significantly increased in all experimental groups compared to the control, with the highest levels observed in the dual-hit group. The elevated LRRK2 expression correlated with the reduction in ZO-1 and Occludin levels and an increase in inflammatory cytokines IL1-β and TNF-α. A similar pattern of LRRK2 expression was observed in the brain. The dual-hit group exhibited increased Iba-1 expression and a significant loss of dopaminergic neurons. Furthermore, the upregulation of LRRK2 was associated with NF-κB activation and Nrf2 inhibition in the brain. Conclusion: Mild chronic colitis induced by DSS may exacerbate brain inflammation in MPTP-induced PD mice by upregulating LRRK2 expression, leading to NF-κB activation and Nrf2 inhibition. We propose that LRRK2 may play a regulatory role in the NF- κB/Nrf2 interplay in PD.