The G2019S LRRK2 mutation exacerbates α-synuclein and tau neuropathology through divergent pathways in Parkinson's disease models.

Aggregated α-synuclein (αSyn) is a pathological hallmark of Parkinson's disease (PD), yet other protein aggregates, including tau, are commonly observed in PD brains. This suggests that PD is not solely a synucleinopathy but may involve multiple, coexisting proteinopathies. Mutations in LRRK2, particularly the G2019S (GS), are the most common cause of familial PD. LRRK2-PD has been associated with both αSyn and tau pathology; however the mechanistic links between LRRK2 dysfunction and protein aggregation remain incompletely defined. Here we opted to investigate whether LRRK2 contributes to αSyn and tau pathology through common molecular pathways or via distinct cellular mechanisms. Viral vector-mediated αSyn overexpression in GS LRRK2 knock-in mice led to enhanced dopaminergic neurodegeneration, increased phosphorylated αSyn levels, pronounced neuroinflammation, and accumulation of lysosomal proteins, suggesting impaired αSyn clearance and immune activation as key drivers. Human iPSC-derived dopaminergic neurons from GS LRRK2 PD patients mirrored these findings. In contrast viral vector-mediated overexpression of tau in GS LRRK2 knock-in mice promoted tau phosphorylation but did not significantly affect neuroinflammation, lysosomal markers, or neurodegeneration, indicating a primarily cell-autonomous mechanism. Our results reveal a mechanistic divergence in how GS LRRK2 impacts αSyn and tau pathologies, supporting the notion that LRRK2 kinase activity contributes to PD pathogenesis through different pathways, thereby highlighting its potential as a therapeutic target in both familial and sporadic PD.