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

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

doi:10.1172/jci.insight.131093

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.

Highlights

Neurodegenerative diseases are characterized by progressive loss of neurons, but the mechanisms underlying the deleterious spread of neuronal injury remain unclear
We report that extracellular human endogenous retroviruses (HERVs)-K(HML-2) RNA is a potent activator of human TLR8 and murine Tlr7
We investigated the response of murine Tlr7 (mTlr7)-expressing microglia and macrophages [6] to HERV-K RNA, using a synthetic 22-nucleotide containing the GUUGUGU motif (HERV-K) matching the particular HERV-K env region

Summary

Introduction

Neurodegenerative diseases are characterized by progressive loss of neurons, but the mechanisms underlying the deleterious spread of neuronal injury remain unclear. Toll-like receptors (TLRs) play a crucial role in regulating immunity against both pathogens and host-derived molecules [1]. The TIR domain interacts with adapters, such as MyD88, which couple to downstream protein kinases, leading to the activation of transcription factors, such as NF-κB, and inducing genes involved in inflammation [2]. The endogenous ligands involved in TLR activation, associated signaling pathways, and cellular mechanisms by means of which TLRs lead to tissue injury in the different pathological contexts remain elusive

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Conclusion