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

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Proc Natl Acad Sci U S A. 2020 Mar 9. pii: 201906466. doi: 10.1073/pnas.1906466117. [Epub ahead of print] Disruption of cellular proteostasis by H1N1 influenza A virus causes α-synuclein aggregation.

Marreiros R¹, M?ller-Schiffmann A¹, Trossbach SV¹, Prikulis I¹, H?nsch S², Weidtkamp-Peters S², Moreira AR³, Sahu S³, Soloviev I³, Selvarajah S³, Lingappa VR³, Korth C⁴.
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Abstract

Neurodegenerative diseases feature specific misfolded or misassembled proteins associated with neurotoxicity. The precise mechanisms by which protein aggregates first arise in the majority of sporadic cases have remained unclear. Likely, a first critical mass of misfolded proteins starts a vicious cycle of a prion-like expansion. We hypothesize that viruses, having evolved to hijack the host cellular machinery for catalyzing their replication, lead to profound disturbances of cellular proteostasis, resulting in such a critical mass of protein aggregates. Here, we investigated the effect of influenza virus (H1N1) strains on proteostasis of proteins associated with neurodegenerative diseases in Lund human mesencephalic dopaminergic cells in vitro and infection of Rag knockout mice in vivo. We demonstrate that acute H1N1 infection leads to the formation of α-synuclein and Disrupted-in-Schizophrenia 1 (DISC1) aggregates, but not of tau or TDP-43 aggregates, indicating a selective effect on proteostasis. Oseltamivir phosphate, an antiinfluenza drug, prevented H1N1-induced α-synuclein aggregation. As a cell pathobiological mechanism, we identified H1N1-induced blocking of autophagosome formation and inhibition of autophagic flux. In addition, α-synuclein aggregates appeared in infected cell populations connected to the olfactory bulbs following intranasal instillation of H1N1 in Rag knockout mice. We propose that H1N1 virus replication in neuronal cells can induce seeds of aggregated α-synuclein or DISC1 that may be able to initiate further detrimental downstream events and should thus be considered a risk factor in the pathogenesis of synucleinopathies or a subset of mental disorders. More generally, aberrant proteostasis induced by viruses may be an underappreciated factor in initiating protein misfolding.


KEYWORDS:

DISC1; Parkinson’s disease; influenza; protein misfolding; α-synuclein

PMID: 32152117 DOI: 10.1073/pnas.1906466117