Lrrk2 p.G2019S-mutant farelerde yüksek fosforile alfa-sinüklein ve fosforile tau influenza A pnömoniti takiben

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ABSTRACT 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 Lrrk2 G2019S or kinase-dead Lrrk2 D1994S 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 pSer 129 α-synuclein and pSer 199 tau levels than mock-treated, mutant mice ( PConclusion Homozygous Lrrk2 G2019S -mutant mice that survived infection by a life-threatening, pneumotropic RNA virus show changes in brain levels of oxidative stress, pSer 199 tau and pSer 129 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.

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