Elevated phosphorylated α-synuclein and phosphorylated tau in Lrrk2 p.G2019S-mutant mice following influenza A pneumonitis
Output Details
Preprint September 22, 2025
Description
Background: Influenza virus exposure elevates the incidence of parkinsonism. We and others previously discovered that allelic variants at the Parkinson's-linked *LRRK2* locus modulate host responses to virulent microbes. Objective: We asked whether *Lrrk2* mutations modify disease outcomes in adult animals following a nasally acquired lung infection. Methods: We inoculated C57BL/6J mice of mutant knock-in *Lrrk2* genotypes with influenza A virus, H1N1-serotype (1 x LD 50 = 2,000 plaque-forming units). Results: During H1N1-induced pneumonitis neither homozygous nor heterozygous mutations of kinase activity-increasing *Lrrk2G2019S* or kinase-dead *Lrrk2D1994S* altered the course of sickness in mice when compared to wild-type littermates, as determined by survival rates, viral titres and weight changes in both sexes. However, six weeks after inoculation brains of H1N1-exposed, homozygous Lrrk2 p.G2019S animals showed higher pSer129 α-synuclein and pSer199 tau levels than mock-treated, mutant mice (P<0.01). The ratios of phosphorylated tau-to-total tau and phosphorylated α-synuclein-to-total α-synuclein also rose in H1N1-exposed Lrrk2 p.G2019S mice (P<0.05). Further, we found that nitrotyrosination of the brain proteome was significantly increased in *Lrrk2G2019S* survivors vs. mock-exposed littermates (P<0.05). Brain H2O2 concentrations were elevated in male, H1N1-inoculated wild-type animals (with a trend seen in females and *Lrrk2G2019S* mice), an effect that was abrogated in kinase-dead *Lrrk2D1994S* mice. Conclusion: Homozygous *Lrrk2G2019S*-mutant mice that survived infection by a life-threatening, pneumotropic RNA virus show changes in brain levels of oxidative stress, pSer199 tau and pSer129 α-synuclein. These results could be of relevance to the initiation of neurodegeneration-linked changes in humans and may help explain differences in the penetrance rate and expressivity of LRRK2 mutants.
