CoChat
Sign Up
Cited by 134Neuroinflammation and Neurodegeneration MechanismsAlzheimer's disease research and treatmentsImmune Response and Inflammation

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

Open access
Dembny, Paul, Newman, Andrew G., Singh, Manvendra, Hinz, Michael, Szczepek, Michal, Krüger, Christina, Adalbert, Robert, Dzaye, Omar +18 more·2020·JCI Insight
DOI 10.1172/jci.insight.131093PMC PMC7205273

Published version of a preprint

Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1172/jci.insight.131093

Cites

4 of 4 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 23

  1. [30]Golbe LI. Progressive supranuclear palsy. Semin Neurol. 2014;34(2):151–159.
  2. [31]Coufal NG, et al. L1 retrotransposition in human neural progenitor cells. Nature. 2009;460(7259):1127–1131.
  3. [32]Scheckel C, et al. Regulatory consequences of neuronal ELAV-like protein binding to coding and non-coding RNAs in human brain. Elife. 2016;5:e10421.
  4. [34]Saugstad JA, et al. Analysis of extracellular RNA in cerebrospinal fluid. J Extracell Vesicles. 2017;6(1):1317577.
  5. [35]Subramanian RP, Wildschutte JH, Russo C, Coffin JM. Identification, characterization, and comparative genomic distribution of the HERV-K (HML-2) group of human endogenous retroviruses. Retrovirology. 2011;8:90.
  6. [36]Grandi N, Tramontano E. Human endogenous retroviruses are ancient acquired elements still shaping innate immune respons- es. Front Immunol. 2018;9:2039.
  7. [37]Mortelmans K, Wang-Johanning F, Johanning GL. The role of human endogenous retroviruses in brain development and func- tion. APMIS. 2016;124(1-2):105–115.
  8. [38]Li W, et al. Human endogenous retrovirus-K contributes to motor neuron disease. Sci Transl Med. 2015;7(307):307ra153.
  9. [39]Lehmann SM, et al. Extracellularly delivered single-stranded viral RNA causes neurodegeneration dependent on TLR7. J Immu- nol. 2012;189(3):1448–1458.
  10. [40]Stocking C, Kozak CA. Murine endogenous retroviruses. Cell Mol Life Sci. 2008;65(21):3383–3398.
  11. [41]Carty M, Goodbody R, Schröder M, Stack J, Moynagh PN, Bowie AG. The human adaptor SARM negatively regulates adap- tor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006;7(10):1074–1081.
  12. [42]Fuentes DR, Swigut T, Wysocka J. Systematic perturbation of retroviral LTRs reveals widespread long-range effects on human gene regulation. Elife. 2018;7:e35989.
  13. [43]Pontis J, et al. Hominoid-specific transposable elements and KZFPs facilitate human embryonic genome activation and control transcription in naive human ESCs. Cell Stem Cell. 2019;24(5):724–735.e5.
  14. [44]Sun W, Samimi H, Gamez M, Zare H, Frost B. Pathogenic tau-induced piRNA depletion promotes neuronal death through transposable element dysregulation in neurodegenerative tauopathies. Nat Neurosci. 2018;21(8):1038–1048.
  15. NMNAT2-deficient axons. Cell Rep. 2015;10(12):1974–1981.
  16. [46]Roberson SM, Walker WS. Immortalization of cloned mouse splenic macrophages with a retrovirus containing the v-raf/mil and v-myc oncogenes. Cell Immunol. 1988;116(2):341–351.
  17. Med. 2012;18(12):1812–1819.
  18. [48]Hoffmann O, et al. TLR2 mediates neuroinflammation and neuronal damage. J Immunol. 2007;178(10):6476–6481.
  19. [49]Saito T. In vivo electroporation in the embryonic mouse central nervous system. Nat Protoc. 2006;1(3):1552–1558.
  20. [50]Lois C, Hong EJ, Pease S, Brown EJ, Baltimore D. Germline transmission and tissue-specific expression of transgenes delivered by lentiviral vectors. Science. 2002;295(5556):868–872.
  21. [51]Mayer J, Sauter M, Rácz A, Scherer D, Mueller-Lantzsch N, Meese E. An almost-intact human endogenous retrovirus K on human chromosome 7. Nat Genet. 1999;21(3):257–258.
  22. [52]Boller K, et al. Evidence that HERV-K is the endogenous retrovirus sequence that codes for the human teratocarcinoma-derived retrovirus HTDV. Virology. 1993;196(1):349–353.
  23. Chem. 2007;282(44):32311–32319.

Cited by

Sorted by citations

Authors
Dembny, P., Newman, A. G., Singh, M., Hinz, M., Szczepek, M., Krüger, C., Adalbert, R., Dzaye, O., Trimbuch, T., Wallach, T., Kleinau, G., Derkow, K., Richard, B. C., Schipke, C., Scheidereit, C., Stachelscheid, H., Golenbock, D., Peters, O., Coleman, M., Heppner, F. L., Scheerer, P., Tarabykin, V., Ruprecht, K., Izsvák, Z., Mayer, J., & Lehnardt, S.
Affiliations
  • Humboldt-Universität zu Berlin (DE)
  • Max Delbrück Center (DE)
  • Royal Veterinary College, London, United Kingdom.
  • NeuroCure Cluster of Excellence (DE)
  • Department of Neuropathology,
  • German Center for Neurodegenerative Diseases (DE)
  • University of Massachusetts Chan Medical School (US)
  • Babraham Institute (GB)
  • Saarland University (DE)
Corresponding author
Lehnardt, Seija
ORCID
Venue
JCI Insight
Publisher
American Society for Clinical Investigation
Published
2020-04-09
Volume
5
Issue
7
ISSN
2379-3708 (ISSN-L)
DOI
10.1172/jci.insight.131093
PMC
PMC7205273
OpenAlex
W3015549321
Cited by
134
References
4
Citations by year
2026: 14 · 2025: 30 · 2024: 26 · 2023: 24 · 2022: 16 · 2021: 21 · 2020: 3
FWCI
6.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • JCI Insight (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • SZTE Publicatio Repozitórium (University of Szeged) (acceptedVersion)
  • eScholarship@UMassChan (submittedVersion)
  • MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
  • DZNE Pub (submittedVersion)
Funders
  • Deutsche Forschungsgemeinschaft, Germany (LE 2420/2-1,SFB-TRR167/B3,NeuroCure Exc 257)
  • Deutsche Forschungsgemeinschaft (SFB740/B6,SFB1078/B6)
  • European Research Council (ERC-2011-ADG 294742)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
HERV-K(HML-2), human endogenous retroviruses, TLR8, TLR7, neurodegeneration, Alzheimer's disease, microglia, cerebrospinal fluid, retroviral RNA, APP/PS1 mice, endogenous ligands
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Humans, Membrane Glycoproteins, RNA, Viral, Mice, Knockout, Endogenous Retroviruses, Toll-Like Receptor 7, Toll-Like Receptor 8, Mice

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review