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| Item Type: | Article |
|---|---|
| Title: | Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors |
| Creators: |
Dembny, P., Newman, A.G.  ORCID: https://orcid.org/0000-0002-0222-9162, Singh, M. ORCID: https://orcid.org/0000-0002-8626-5418, Hinz, M. ORCID: https://orcid.org/0000-0003-2611-4121, Szczepek, M., Krüger, C., Adalbert, R., Dzaye, O., Trimbuch, T. ORCID: https://orcid.org/0000-0001-7512-8955, Wallach, T., Kleinau, G., Derkow, K., Richard, B.C., Schipke, C. ORCID: https://orcid.org/0000-0002-1105-1853, Scheidereit, C. ORCID: https://orcid.org/0000-0002-0446-6129, Stachelscheid, H., Golenbock, D., Peters, O. ORCID: https://orcid.org/0000-0003-0568-2998, Coleman, M., Heppner, F.L., Scheerer, P., Tarabykin, V., Ruprecht, K., Izsvák, Z. ORCID: https://orcid.org/0000-0002-2053-2384, Mayer, J. and Lehnardt, S.
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| 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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