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

Item Type:Article
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 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 Stachelscheid, H. 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, such as HERV-K(HML-2), are reported to be involved in neurological disorders, little is known about their biological function. We report that RNA from an HERV-K(HML-2) envelope gene region binds to and activates human Toll-like receptor (TLR) 8, as well as murine Tlr7, expressed in neurons and microglia, thereby causing neurodegeneration. HERV-K(HML-2) RNA introduced 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 and microglia accumulation. Tlr7-deficient mice were protected against neurodegenerative effects but were resensitized toward HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Transcriptome data sets of human AD brain samples revealed a distinct correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from individuals with AD compared with controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for species-specific TLRs 7/8 and imply a functional contribution of human endogenous retroviral transcripts to neurodegenerative processes, such as AD.
Keywords:Animals, Mice
Source:JCI Insight
ISSN:2379-3708
Publisher:American Society for Clinical Investigation
Volume:5
Number:7
Page Range:e131093
Date:9 April 2020
Official Publication:https://doi.org/10.1172/jci.insight.131093
External Fulltext:View full text on PubMed Central
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/18363/Preprint version

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