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

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly 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. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

Preferential nuclear compartmentalization of endogenous mink cell focus-forming-related retroviral transcripts.

Endogenous mink cell focus-forming (MCF)-like retroviral sequences in the murine genome are stable, inherited sequences analogous to other chromosomal genes. As such, it is thought that they are transcribed and translated in a manner analogous to other genes. However, when the SL12.4 CD4-, CD8- thymoma cell line was studied for nuclear/cytoplasmic distribution of endogenous MCF-related transcripts, there was a nuclear predominance. The great majority of full-length 8.4-kb endogenous MCF-related transcripts were nuclear. Even the smaller, spliced 3.0-kb transcripts were at least as prominent in the nucleus as the cytoplasm, whereas cellular RNA was 80% cytoplasmic and other cellular transcripts were represented in the cytoplasm to a much greater extent than the nucleus. Size cannot fully account for the nuclear presence of MCF-related endogenous transcripts, because the 3.0-kb MCF transcripts occurred in the nucleus to a much greater relative extent than 3.8-kb c-myb transcripts. These studies point to retroviral-like structures of these transcripts as influencing their intracellular compartmentalization.