LRRK2(R1627P) mutation amplifies environmental risk factors induced chronic inflammation and α-synuclein aggregation in the gut of rats.

Chronic intestinal inflammation is a key precursor to Parkinson's disease (PD). Leucine-rich repeat kinase 2 R1628P variant (LRRK2(R1628P)) is a risk factor for PD in Asians. However, whether it drives the occurrence of intestinal inflammation remains elusive. Here, we report that LRRK2(R1627P) (the rat homolog) disrupts intestinal homeostasis during aging and toxin exposure in rats. Compared with age-matched wild-type rats, aging LRRK2(R1627P) rats exhibited shortened small intestine, reduced goblet cells, and abnormal epithelial cell junction structures. Mechanistically, these changes were induced by macrophage polarization toward a pro-inflammatory phenotype via TLR4/MyD88/NF-κB pathway, resulting in PD-associated intestinal pathology, including chronic inflammatory, decreased microbial diversity, and increased p-α-synuclein aggregation. LRRK2(R1627P) also enhanced susceptibility to lipopolysaccharide-induced intestinal inflammation. Remarkably, TLR4 inhibitor ameliorated the age-related disruption of intestinal homeostasis mediated by LRRK2(R1627P). Using the LRRK2(R1627P) rats, this study reveals a cascading interplay among genetic susceptibility, age-related internal imbalance, and exogenous toxin exposure in PD pathology. These findings provide critical insights into how the dynamic interplay of multiple risk factors overwhelms the body's compensatory thresholds, ultimately initiating the pathological process of neurodegeneration.