Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors
Paul Dembny, Andrew G. Newman, Manvendra Singh, Michael Hinz, Michal Szczepek, Christina Krüger, Robert Adalbert, Omar Dzaye, Thorsten Trimbuch, Thomas Wallach, Gunnar Kleinau, Katja Derkow, Bernhard C. Richard, Carola Schipke, Claus Scheidereit, Harald Stachelscheid, Douglas Golenbock, Oliver Peters, Michael Coleman, Frank L. Heppner, Patrick Scheerer, Victor Tarabykin, Klemens Ruprecht, Zsuzsanna Izsvák, Jens Mayer, Seija Lehnardt
Paul Dembny, Andrew G. Newman, Manvendra Singh, Michael Hinz, Michal Szczepek, Christina Krüger, Robert Adalbert, Omar Dzaye, Thorsten Trimbuch, Thomas Wallach, Gunnar Kleinau, Katja Derkow, Bernhard C. Richard, Carola Schipke, Claus Scheidereit, Harald Stachelscheid, Douglas Golenbock, Oliver Peters, Michael Coleman, Frank L. Heppner, Patrick Scheerer, Victor Tarabykin, Klemens Ruprecht, Zsuzsanna Izsvák, Jens Mayer, Seija Lehnardt
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Research Article Immunology Neuroscience

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

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.

Authors

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

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Figure 5

Transfection of murine Tlr7 or human TLR8 restores neurodegenerative effects of HERV-K RNA in vivo.

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Transfection of murine Tlr7 or human TLR8 restores neurodegenerative eff...
(A) Tlr7-KO mouse embryos (E14.5) were electroporated in utero with an expression vector for murine Tlr7 (Tlr7/GFP, left), an expression vector for human TLR8 (TLR8/GFP, middle) or control (co/RFP [tdTomato], right). EGFP was coexpressed from an IRES cassette. At postnatal day 19, 10 μg of HERV-K RNA (Tlr7 vector, n = 5; TLR8 vector, n = 5; control vector, n = 6) or mutant oligoribonucleotide (Tlr7 vector, n = 5; TLR8 vector, n = 5; control vector, n = 6) were administered intrathecally. Cerebral cortex was analyzed by immunostaining with NeuN antibody 3 days later. Scale bar: 50 μm. (B) Quantitation of GFP+/Tomato+ NeuN+ cells (left) and GFP−/Tomato– NeuN+ cells (right) in the electroporated cortex. (C) Sections of the electroporated cortex were immunostained with active caspase-3 antibody, and caspase-3+ cells were quantified. Results are presented as mean ± SEM. One-way ANOVA test yielded (B) P = 0.0014 (left) and n.s. (right) and (C) P < 0.0001 over all groups. Indicated P values were determined by 1-way ANOVA with Bonferroni’s post hoc test. n.s., not significant.