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 4

Intrathecal administration of HERV-K RNA causes neurodegeneration through Tlr7.

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Intrathecal administration of HERV-K RNA causes neurodegeneration throug...
Ten micrograms of HERV-K, HERV-K (-GU), or mutant oligoribonucleotide was injected intrathecally into WT [HERV-K, n = 5–6; HERV-K (-GU), n = 4; mutant oligoribonucleotide, n = 4–5] or Tlr7-KO mice [HERV-K, n = 5–6; HERV-K (-GU), n = 4; mutant oligoribonucleotide, n = 4–5] mice. (A–C) After 3 days, brain sections were immunostained with neurofilament antibody (A, scale bar: 50 μm), NeuN antibody (B), or active caspase-3 antibody (C) and DAPI. NeuN-positive (B) and caspase-3–positive (C) cortical cells were quantified. (D and E) After 14 days, brain sections were immunostained with NeuN antibody and DAPI (D, scale bar: 10 μm). NeuN-positive cortical cells were quantified (E). (F) HERV-K inhibitor or nonspecific inhibitor (co. inhib.; 125 pmol) was injected intrathecally into WT mice. After 16 hours, mice were injected intrathecally with 10 μg of HERV-K or mutant oligoribonucleotide (HERV-K inhibitor: HERV-K, n = 4; mut. oligo, n = 4; co inhib: HERV-K, n = 4; mut. oligo, n = 4). After further 3 days, brain sections were immunostained with NeuN antibody. NeuN-positive cortical cells were quantified. Results are presented as mean ± SEM. One-way ANOVA test yielded P = 0.0007 (B), P = 0.0003 (C), P < 0.0001 (E), and P = 0.0145 (F) over all groups. Indicated P values were determined by 1-way ANOVA with Bonferroni’s post hoc test. n.s., not significant.