Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors.
Alzheimer’s disease
Immunology
Innate immunity
Neurodegeneration
Neuroscience
Journal
JCI insight
ISSN: 2379-3708
Titre abrégé: JCI Insight
Pays: United States
ID NLM: 101676073
Informations de publication
Date de publication:
09 04 2020
09 04 2020
Historique:
received:
14
06
2019
accepted:
04
03
2020
entrez:
10
4
2020
pubmed:
10
4
2020
medline:
20
5
2021
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32271161
pii: 131093
doi: 10.1172/jci.insight.131093
pmc: PMC7205273
doi:
pii:
Substances chimiques
Membrane Glycoproteins
0
RNA, Viral
0
TLR8 protein, human
0
Tlr7 protein, mouse
0
Toll-Like Receptor 7
0
Toll-Like Receptor 8
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
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