The LRRK2 G2019S mutation is one of the most common genetic risk factors for Parkinson s disease (PD), yet LRRK2 G2019S knock in (KI) mice rarely develop robust neurodegeneration under basal conditions, suggesting that additional environmental triggers are required for disease progression. Here, we established a clinically relevant gene environment interaction mouse model of PD by subjecting LRRK2 G2019S KI mice to recurrent Citrobacter (C.) rodentium infection, a murine model of enteric bacterial inflammation. Repeated infection induced progressive PD like phenotypes selectively in KI mice, including motor impairment, reduced locomotor activity, impaired motor coordination, selective nigrostriatal dopaminergic neurodegeneration, enhanced neuroinflammation, and pathological phosphorylated alpha-synuclein (p alpha Syn) accumulation, whereas wild type (WT) mice remained largely resistant. Mechanistically, infected KI mice developed markedly exacerbated colonic inflammation, epithelial barrier dysfunction, increased intestinal permeability, and enhanced inflammasome activation despite normal bacterial clearance, indicating that pathogenic LRRK2 signaling amplifies inflammatory responses rather than impairing antimicrobial defense. In parallel, recurrent infection induced pronounced intestinal p alpha Syn accumulation and expansion of pathology beyond the epithelial layer in KI mice, supporting a gut brain axis mechanism linking intestinal inflammation to neurodegeneration. Collectively, these findings demonstrate that the LRRK2 G2019S mutation functions as a sensitizing factor that cooperates with recurrent enteric inflammation to drive PD related pathology. This study establishes a physiologically relevant LRRK2 G2019S gene environment interaction mouse model that recapitulates key behavioral, neuropathological, and inflammatory features of PD.
Wang, Y., Weber, M. A., Stodden, N., Ziebarth, L., Lingappa, S., Borjabustamante, M., Balakrishnan, T., Jaily, M., Sakaguchi, T., Thangavel, R., Wen, W., Luo, J., Narayanan, N., Kang, Z.
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