Paul Dembny, Andrew G. Newman, Manvendra K Singh, M. Hinz, M. Szczepek, C. Krüger, R. Adalbert, O. Dzaye, T. Trimbuch, T. Wallach, G. Kleinau, K. Derkow, B. C. Richard, C. Schipke, C. Scheidereit, H. Stachelscheid, D. Golenbock, O. Peters, M. Coleman, F. Heppner, P. Scheerer, V. Tarabykin, K. Ruprecht, Z. Izsvák, J. Mayer, S. Lehnardt
JCI insight, 2020
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.
Cited by 9 publications.
Field of study: Medicine