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 3

Endogenous HERV-K transcripts trigger neurodegeneration.

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Endogenous HERV-K transcripts trigger neurodegeneration. (A) SH-SY5Y cel...
(A) SH-SY5Y cells and (B) virion particles isolated from Tera-1 cells were analyzed by RT-PCR using primers amplifying an HERV-K env region harboring the motif GUUGUGU. Tera-1 cells served as a positive control. (C) WT and Tlr7-KO neurons were incubated with 10 μL suspension of Tera-1 virions or left untreated (control) for 6 days. Relative neuronal viability was determined (P < 0.0001 over all groups, Kruskal-Wallis test) (n = 6–10). (D) WT neurons were incubated with 10 μL suspension of Tera-1 virions for 6 days, with or without HERV-K inhibitor. A nonspecific inhibitor served as a negative control. Relative neuronal viability was assessed (P < 0.0001 over all groups, Kruskal-Wallis test) (n = 5–10). (E) Supernatants (S/N) from untreated and apoptotic neurons treated with staurosporine were analyzed by RT-PCR for HERV-K expression. (F) For 4 days,20 μg/mL RNA from untransfected SH-SY5Y cells (control) or SH-SY5Y cells overexpressing HERV-K RNA harboring a GUUGUGU motif [HERV-K (+ GU)], a GUUGCGU motif (HERV-K young), or the respective antisense sequence were used for incubation of SH-SY5Y cells with or without HERV-K inhibitor. Untreated SH-SY5Y cells served as negative control, and TL8-506 served as positive control. Relative neuronal viability was assessed (P = 0.0001 over all groups, Kruskal-Wallis test). Results are presented as mean ± SEM. *P < 0.05, and **P < 0.01 compared with control (n = 5). Indicated P values were determined by Kruskal-Wallis test with Dunn’s post hoc analysis.