Reactivated endogenous retroviruses promote protein aggregate spreading

Shu Liu, Stefanie-Elisabeth Heumüller, André Hossinger, Stephan A. Müller, Oleksandra Buravlova, Stefan F. Lichtenthaler, Philip Denner and Ina M. Vorberg ()
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Shu Liu: German Center for Neurodegenerative Diseases Bonn (DZNE)
Stefanie-Elisabeth Heumüller: German Center for Neurodegenerative Diseases Bonn (DZNE)
André Hossinger: German Center for Neurodegenerative Diseases Bonn (DZNE)
Stephan A. Müller: German Center for Neurodegenerative Diseases (DZNE)
Oleksandra Buravlova: German Center for Neurodegenerative Diseases Bonn (DZNE)
Stefan F. Lichtenthaler: German Center for Neurodegenerative Diseases (DZNE)
Philip Denner: German Center for Neurodegenerative Diseases Bonn (DZNE)
Ina M. Vorberg: German Center for Neurodegenerative Diseases Bonn (DZNE)

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Prion-like spreading of protein misfolding is a characteristic of neurodegenerative diseases, but the exact mechanisms of intercellular protein aggregate dissemination remain unresolved. Evidence accumulates that endogenous retroviruses, remnants of viral germline infections that are normally epigenetically silenced, become upregulated in neurodegenerative diseases such as amyotrophic lateral sclerosis and tauopathies. Here we uncover that activation of endogenous retroviruses affects prion-like spreading of proteopathic seeds. We show that upregulation of endogenous retroviruses drastically increases the dissemination of protein aggregates between cells in culture, a process that can be inhibited by targeting the viral envelope protein or viral protein processing. Human endogenous retrovirus envelopes of four different clades also elevate intercellular spreading of proteopathic seeds, including pathological Tau. Our data support a role of endogenous retroviruses in protein misfolding diseases and suggest that antiviral drugs could represent promising candidates for inhibiting protein aggregate spreading.

Date: 2023
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DOI: 10.1038/s41467-023-40632-z

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