Peripheral Immune Challenge Drives Enteric α-Synuclein and Tau Pathology in LRRK2 G2019S Mice.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by α-synuclein aggregation and dopaminergic neuron loss. Non-motor symptoms, including gastrointestinal dysfunction, often precede motor onset, suggesting a gut origin of pathology. LRRK2 variants increase susceptibility to both PD and Crohn's disease, pointing to a potential link between LRRK2 hyperactivity and early intestinal abnormalities; however, it remains unclear how LRRK2 contributes to enteric α-synuclein pathology and co-occurring proteinopathies. In this study, we investigated the interaction between chronic peripheral inflammation and the LRRK2 G2019S variant using a longitudinal mouse model combining ageing and repeated low-dose LPS exposure. We quantified peripheral cytokine levels, colonic immune cell infiltration (CD4⁺ T cells and macrophages), and the temporal progression of enteric α-synuclein and tau pathology across different ages. Our results showed that chronic LPS exposure induced an age-dependent increase in circulating cytokines and colonic immune infiltration in LRRK2 G2019S mice, accompanied by enhanced enteric α-synuclein accumulation and phosphorylation, alongside elevated tau phosphorylation, compared with wild-type controls. Notably, total neuronal counts remained stable, indicating a distinct pre-degenerative stage of pathology. Overall, our findings demonstrate that chronic peripheral inflammation synergizes with LRRK2 G2019S to trigger early intestinal inflammation and α-synuclein/tau co-pathology in the absence of overt neurodegeneration. These results suggest that LRRK2 acts as a critical link between systemic immunity and neuronal protein homeostasis, increasing the vulnerability of the gut to inflammatory stress. Characterizing this early pathological window provides key insights into PD initiation and highlights the gut as a promising target for early therapeutic intervention.