Ever since our ancestors were infected with retroviruses millions of years ago, we have carried the components of these viruses in our genes, the human endogenous retrovirus (HERV). These viral components have evolved to lose the ability to replicate and infect, but they are an integral part of our genetic makeup. In fact, humans have five times more HERV in the non-coding part than the coding gene.
So far, there has been strong concern about the correlation between HERV and the onset or progression of the disease. This is why the expression of HERV has been studied in samples of pathological origin. Although extensively studied, the biological function and disease associations of HERV are largely elusive. For example, previous studies have not provided conclusions about whether HERV is a cause or a consequence of the disease.
Now, in a new study, researchers from Germany and the United States have successfully demonstrated for the first time the negative effects of HERV activation on human brain development, using new techniques that allow people to gain a deeper understanding of the mechanisms of action and functions of HERV. The findings were recently published in the journal Cell Stem Cell under the title "Activation of HERV-K (HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3."
Using CRISPR technology, the authors activated a specific set of HERVs called HERV-K (HML-2) in human embryonic stem cells and had these stem cells produce neurons. HERV-K (HML-2) is associated with neurotoxicity, but there is no clear understanding of its basis for action or mechanism. They found that transcriptional activation of HERV-K (HML-2) highly activates the NTRK3 gene and other neurodegenerative-related genes involved in brain development. As a result, cortical neurons, the nerve cells in our cerebral cortex, completely lose their function. Higher HERV-K (HML-2) transcription alters cortical formation in forebrain organoids. They develop very differently from healthy neurons in this brain region--- axons (extensions of nerve cells) are much shorter and branch much less. Therefore, the activation of HERV-K (HML-2) impairs the development of cortical neurons and ultimately affects the development of the brain.
The authors also found that direct activation of NTRK3 is phenotypically similar to HERV-K (HML-2) activation, and that lowering levels of NTRK3 in the context of HERV-K (HML-2) activation restores differentiation of cortical neurons.
The study notes that transcriptional activation of HERV-K (HML-2) is detrimental to the development and function of cortical neurons, but this effect is specific to cell types because dopaminergic neurons are not affected.
Mechanisms by which activation of HERV-K (HML-2) leads to impaired cortex development, Source Cell Stem Cell, 2021, doi:10.1016/j.stem.2021.04.009
Since neurodegenerative diseases are often associated with activation of several groups of HERVs, the negative impact of HERV activation on the development of neurons in the cortex is an important finding. It has been known that environmental factors such as viruses, bacteria, and ultraviolet light can activate different HERVs, which can lead to the development of disease. This knowledge, in turn, makes HERV more meaningful in clinical applications. Shutting down different HERVs could open up a new area of research for treating patients with neurodegenerative diseases. Next, the authors will study the effects of HERV inactivation on neurons in the context of disease.
In addition, these findings provide important indications that epigenetic mechanisms allow HERV to be controlled in healthy brain development. The authors even speculate that controlled HERV has a functional role in normal brain development. They point out that humans have been carrying HERVs for about 40 to 70 million years, and speculate that their existence is related to the natural processes of humans, otherwise humans would not have retained them for so long in the process of evolution. Further basic research in this direction may reveal new features of HERV. (Bio Valley Bioon.com)
Resources:
Vidya Padmanabhan Nair et al, Activation of HERV-K(HML-2) disrupts cortical patterning and neuronal differentiation by increasing NTRK3. Cell Stem Cell, 2021, doi:10.1016/j.stem.2021.04.009.