Progranulin is increased during prodromal pathology in LRRK2 G2019S mice

The leucine-rich repeat kinase 2 (LRRK2) G2019S mutation is a major genetic risk factor for Parkinson's disease (PD). Most studies have shown that this mutation alone is insufficient to induce marked motor impairment or notable dopaminergic loss, and that pathological changes have been reported mainly in aging models or when additional stressors are applied. A decrease in progranulin (PGRN) is a major cause of frontotemporal dementia and has also been observed in patients with LRRK2 G2019S PD. In this study, we sought to determine how PGRN is regulated during the prodromal stage of PD. In 12-week-old female G2019S mice, overt degeneration of nigral dopaminergic neurons or motor impairments was not observed; however, these mice exhibited increased non-motor behavior. Pathological analyses revealed elevated NOD-like receptor protein 3 (NLRP3) inflammasome activation and Iba-1 expression. Additionally, abnormal protein accumulation was observed in the brain. Notably, PGRN levels increased in both brain tissue and plasma, accompanied by a concurrent reduction in elastase expression in the brains of G2019S mice. Increased levels of PGRN and its colocalization with phosphorylated LRRK2 were also observed in primary microglia derived from day-1 pups. Collectively, our findings demonstrate that PGRN is upregulated during the prodromal stage of pathology and the emergence of non-motor symptoms in young LRRK2 G2019S transgenic mice. This early increase in PGRN, which occurs alongside neuroinflammation and abnormal protein accumulation, suggests that PGRN regulation may follow a stage-dependent trajectory and provides new insights into the initial pathogenic processes associated with LRRK2 G2019S-linked PD.