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

Dembny, P.; Newman, A. G.; Singh, M.; Hinz, M.; Szczepek, M.; Krüger, C.; Adalbert, R.; al-Dzaye, O.; Trimbuch, T.; Wallach, T.; Kleinau, G.; Derkow, K.; Richard, B. C.; Schipke, C.; Scheidereit, C.; Golenbock, D.; Peters, O.; Coleman, M.; Heppner, F. L.; Scheerer, P.; Tarabykin, V.; Ruprecht, K.; Izsvak, Z.; Mayer, J.; Lehnardt, S.

doi:10.1101/721241

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bioRxiv · 10.1101/721241

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

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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.

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Dembny, P., Newman, A. G., Singh, M., Hinz, M., Szczepek, M., Krüger, C., Adalbert, R., al-Dzaye, O., Trimbuch, T., Wallach, T., Kleinau, G., Derkow, K., Richard, B. C., Schipke, C., Scheidereit, C., Golenbock, D., Peters, O., Coleman, M., Heppner, F. L., Scheerer, P., Tarabykin, V., Ruprecht, K., Izsvak, Z., Mayer, J., Lehnardt, S.. 2019-08-01. Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors. https://doi.org/10.1101/721241

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