Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation

Abstract

Significance Synucleinopathies such as Parkinson’s disease feature deposition of misfolded α-synuclein. It is likely that cellular proteostasis compensates for misfolded α-synuclein to some extent, but, once exhausted, α-synuclein can form seeds for a prion-like spread in the brain. Here, we demonstrate that, in human dopaminergic neurons and in mouse brain, H1N1 influenza virus induces aggregation of α-synuclein by blocking protein degradation pathways. Following intranasal instillation, H1N1 spreading along the olfactory route into brain areas mimics α-synuclein deposits in synucleinopathies. H1N1 may therefore be considered a risk factor for synucleinopathies that could potentially be minimized by regular vaccination. On the contrary, H1N1 tropism for olfactory epithelium suggests that live attenuated virus vaccines should be investigated for possible long-term effects on protein misfolding.