LRRK2P1446L/MAPTR5H rare variants drive interferon-mediated neuroinflammation and gut microbiota dysregulation in Parkinson’s disease

Unlike classic Parkinson’s disease (PD) cases, some PD cases result from a digenic variant combination, with complex clinical manifestations and unclear molecular mechanisms. We identified a familial PD patient carrying heterozygous LRRK2 P1446L and MAPT R5H variants. Patient-derived induced pluripotent stem cells (iPSCs), knock-in mouse models, and dopaminergic cell lines were used to investigate the molecular and phenotypic consequences of these mutations. Transcriptomic and 16 S microbiome analyses were performed to elucidate the underlying pathogenic pathways. The proband exhibited early-onset, rapidly progressive PD characterized by motor dysfunction, cognitive decline, and severe constipation. iPSC-derived dopaminergic neurons from the patient presented reduced tyrosine hydroxylase (TH) expression and elevated levels of phosphorylated α-synuclein and inflammatory cytokines. Compared to mice with a single genetic mutation, the LRRK2 P1446L / MAPT R5H digenic mutant combination displayed aggravated motor deficits, dopaminergic neuron loss, and α-synuclein aggregation. Transcriptomic profiling of midbrain tissues revealed strong activation of type I interferon signalling mediated by the STING–TBK1–IRF3 pathway, which was further validated in mutant dopaminergic cells. Moreover, gut microbiota analyses revealed pronounced dysbiosis in digenic mutant mice, characterized by increased Alloprevotella and Lactobacillaceae abundance and decreased Akkermansiaceae abundance. Together, these results indicate that LRRK2 P1446L / MAPT R5H variant combination is associated with dopaminergic degeneration, interferon-mediated neuroinflammation, and gut–brain axis disruption in Parkinson’s Disease.