Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Paul Dembny; Andrew G. Newman; Manvendra Singh; Michael Hinz; Michal Szczepek; Christina Krüger; Róbert Adalbert; Omar Dildar a Dzaye; Thorsten Trimbuch; Thomas E. Wallach; Gunnar Kleinau; Katja Derkow; Bernhard Clemens Richard; Carola G. Schipke; Claus Scheidereit; Harald Stachelscheid; Douglas Taylor Golenbock; Oliver Peters; Michael P. Coleman; Frank L. Heppner; Patrick Scheerer; Victor S. Tarabykin; Klemens Ruprecht; Zsuzsanna Izsvák; Jens M. Mayer; Seija Lehnardt

doi:10.1172/jci.insight.131093

NeuroscienceJCI InsightApr 8, 2020

Peer-reviewed journal article

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Paul Dembny iD, Andrew G. Newman iD, Manvendra Singh iD, Michael Hinz, Michal Szczepek iD, Christina Krüger iD, Róbert Adalbert iD, Omar Dildar a Dzaye iD, Thorsten Trimbuch iD, Thomas E. Wallach iD, Gunnar Kleinau iD, Katja Derkow, Bernhard Clemens Richard iD, Carola G. Schipke iD, Claus Scheidereit iD, Harald Stachelscheid iD, Douglas Taylor Golenbock iD, Oliver Peters iD, Michael P. Coleman iD, Frank L. Heppner iD, Patrick Scheerer iD, Victor S. Tarabykin iD, Klemens Ruprecht iD, Zsuzsanna Izsvák iD, Jens M. Mayer iD, Seija Lehnardt iD

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Abstract

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimers disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.