Neural Cell Responses Upon Exposure to Human Endogenous Retroviruses

Abstract

Human endogenous retroviruses (HERVs) are ancient retroviral elements, which invaded the human germ line several million years ago. Subsequent retrotransposition events amplified these sequences, resulting in approximately 8% of the human genome being composed of HERV sequences today. These genetic elements, normally dormant within human genomes, can be (re)-activated by environmental factors such as infections with other viruses, leading to the expression of viral proteins and, in some instances, even to viral particle production. Several studies have shown that the expression of these retroviral elements correlates with the onset and progression of neurological diseases such as multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS). Further studies provided evidence on additional roles for HERVs in schizophrenia (SCZ). Since these diseases are still not well understood, HERVs might constitute a new category of pathogenic components that could significantly change our understanding of these pathologies. Moreover, knowledge about their mode of action might also help to develop novel and more powerful approaches for the treatment of these complex diseases. Therefore, the main scope of this review is a description of the current knowledge on the involvement of HERV-W and HERV-K in neurological disease specifically focusing on the effects they exert on neural cells of the central nervous system.

Keywords: glia; human endogenous retrovirus; mobile genetic elements; neurodegenerative diseases; neurons.

Figure 1

HERV-mediated effects on neural cells. This illustration summarizes origin and observed molecular effects of HERW-W and HERV-K on cells of the central nervous system. Arrow starting points indicate cellular sources of HERV particles or proteins (red dots), whereas arrowheads point to influenced cell types. Modulated processes are shown in gray boxes, and regulated molecules are highlighted in red next to each cell type. The question mark next to TDP-43 refers to its postulated regulation in neurons. Whether microglia and astroglia respond to HERVs in an auto- and/or paracrine way and whether neurons react to internal and/or extracellular HERVs remains to be shown. OPCs: oligodendroglial progenitor cells; NO: nitric oxide; CRP: C-reactive protein; BDNF: brain-derived neurotrophic factor; DRD3: dopamine receptor D₃; TRPC3: short transient receptor potential channel 3; DISC1: disrupted in schizophrenia 1; TDP-43: TAR DNA-binding protein 43.