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

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Item Type:	Article
Title:	Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors
Creators Name:	Dembny, P., Newman, A.G., Singh, M., Hinz, M., Szczepek, M., Krüger, C., Adalbert, R., Dzaye, O., Trimbuch, T., Wallach, T., Kleinau, G., Derkow, K., Richard, B.C., Schipke, C., Scheidereit, C., Stachelscheid, H., Golenbock, D., Peters, O., Coleman, M., Heppner, F.L., Scheerer, P., Tarabykin, V., Ruprecht, K., Izsvák, Z., 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:	Alzheimer Disease, Animal Disease Models, Endogenous Retroviruses, Knockout Mice, Membrane Glycoproteins, Toll-Like Receptor 7, Toll-Like Receptor 8, Viral RNA, 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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