Highly efficient intercellular spreading of protein misfolding mediated by viral ligand-receptor interactions

Shu Liu, André Hossinger, Stefanie-Elisabeth Heumüller, Annika Hornberger, Oleksandra Buravlova, Katerina Konstantoulea, Stephan A. Müller, Lydia Paulsen, Frederic Rousseau, Joost Schymkowitz, Stefan F. Lichtenthaler, Manuela Neumann, Philip Denner and Ina M. Vorberg ()
Additional contact information
Shu Liu: German Center for Neurodegenerative Diseases Bonn (DZNE)
André Hossinger: German Center for Neurodegenerative Diseases Bonn (DZNE)
Stefanie-Elisabeth Heumüller: German Center for Neurodegenerative Diseases Bonn (DZNE)
Annika Hornberger: German Center for Neurodegenerative Diseases Bonn (DZNE)
Oleksandra Buravlova: German Center for Neurodegenerative Diseases Bonn (DZNE)
Katerina Konstantoulea: VIB Center for Brain and Disease Research
Stephan A. Müller: German Center for Neurodegenerative Diseases (DZNE)
Lydia Paulsen: German Center for Neurodegenerative Diseases Bonn (DZNE)
Frederic Rousseau: VIB Center for Brain and Disease Research
Joost Schymkowitz: VIB Center for Brain and Disease Research
Stefan F. Lichtenthaler: German Center for Neurodegenerative Diseases (DZNE)
Manuela Neumann: University Hospital Tübingen
Philip Denner: German Center for Neurodegenerative Diseases Bonn (DZNE)
Ina M. Vorberg: German Center for Neurodegenerative Diseases Bonn (DZNE)

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Protein aggregates associated with neurodegenerative diseases have the ability to transmit to unaffected cells, thereby templating their own aberrant conformation onto soluble homotypic proteins. Proteopathic seeds can be released into the extracellular space, secreted in association with extracellular vesicles (EV) or exchanged by direct cell-to-cell contact. The extent to which each of these pathways contribute to the prion-like spreading of protein misfolding is unclear. Exchange of cellular cargo by both direct cell contact or via EV depends on receptor-ligand interactions. We hypothesized that enabling these interactions through viral ligands enhances intercellular proteopathic seed transmission. Using different cellular models propagating prions or pathogenic Tau aggregates, we demonstrate that vesicular stomatitis virus glycoprotein and SARS-CoV-2 spike S increase aggregate induction by cell contact or ligand-decorated EV. Thus, receptor-ligand interactions are important determinants of intercellular aggregate dissemination. Our data raise the possibility that viral infections contribute to proteopathic seed spreading by facilitating intercellular cargo transfer.

Date: 2021
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DOI: 10.1038/s41467-021-25855-2

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