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

Item Type:Preprint
Title:Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors
Creators Name:Dembny, P. and Newman, A.G. and Singh, M. and Hinz, M. and Szczepek, M. and Krüger, C. and Adalbert, R. and al-Dzaye, O. and Trimbuch, T. and Wallach, T. and Kleinau, G. and Derkow, K. and Richard, B.C. and Schipke, C. and Scheidereit, C. and Golenbock, D. and Peters, O. and Coleman, M. and Heppner, F.L. and Scheerer, P. and Tarabykin, V. and Ruprecht, K. and Izsvák, Z. and Mayer, J. and Lehnardt, S.
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 Alzheimer’s 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.
Publisher:Cold Spring Harbor Laboratory Press
Article Number:721241
Date:1 August 2019
Official Publication:https://doi.org/10.1101/721241
Related to:
https://edoc.mdc-berlin.de/18851/Final version

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