Researchers explain how "viral" agents of neurological diseases have ended up in our DNA

July 11, 2019

And if the "environmental" factor missing in some of our most deadly neurological diseases was actually in our genome?

Write in Frontiers in genetics, researchers at the University of Düsseldorf explain how viruses have ended up in our DNA – and what puts them in the context of unresolved diseases such as multiple sclerosis.

The enemy in the interior

About 8% of our DNA comes from viruses. More specifically, retroviruses – not because they are old, but because they reverse the normal process of reading DNA to be written in the genome of their host.

Retrovirus are old though: they began to blend with our early primitive ancestors millions of years ago. Over the millennia, most of their remains in our DNA – called human endogenous retroviruses or HERVs – have been silenced by mutations. Others, who had evolved to protect themselves from rival viruses, formed the prototypical immune system and still protect us from infection.

However, HERV may also be the missing causal link in the major "unresolved" neurological diseases.

HERVs have been implicated in the onset and progression of multiple sclerosis [MS], amyotrophic lateral sclerosis [ALS] and schizophrenia [SCZ]. Sleeping HERVs can be reactivated by environmental factors such as inflammation, mutations, drugs or infection by other viruses, so could provide a mechanism for establishing a well-established epidemiological link with these disorders. "

Patrick Küry, lead author

Role in MS

Until now, the strongest evidence links HERVs to MS.

"Multiple sclerosis is caused by direct autoimmune attacks of myelin – the fat envelope of nerve cells – in the brain and spinal cord," says Küry. "But we still do not understand how these attacks are triggered."

Various studies suggest that reactivation of HERV could be such a trigger.

"Retroviruses were badociated with MS for the first time in 1989, but only decades later, it became clear that it was actually HERV."

"Thereafter, HERV RNA and protein levels – the" readings "of reactivated HERV DNA – have been shown to increase in brain fluid and medullary fluid. [CSF] affected people, as well as in their post-mortem brain tissue.

"By linking this reactivation of HERV to autoimmune attacks in MS, it has been found that HERV proteins can trigger an immune response against myelin, triggering a disease similar to MS in murine models."

Mechanically, HERV proteins could trigger autoimmunity by "molecular mimetic".

"In addition to the direct effects of HERV on myelinating cells, several groups reported structural similarities between HERV and the oligodendrocyte glycoprotein of myelin, a molecule displayed on the surface of myelin. This similarity could induce the immune system into damaging myelin when it attacks HERV. "

Experimental evidence in humans

Similar experiments have linked HERVs to the CIDP, a peripheral demyelinating disease, as well as to more distinct processes, such as the progressive loss of motor neurons in ALS (Lou Gehrig's disease).

In schizophrenia, a complex neurodevelopmental disorder, the link with HERV is more circumstantial.

"It has been reported that HERV proteins increase the expression of genes related to schizophrenia in human brain cells in culture," Küry reports. "However, studies on people with schizophrenia show inconsistent changes in the expression of HERV in blood, CSF, and post-mortem brain tissue compared to healthy controls."

The question of whether HERVs contribute to these unexplained neurological conditions and others needs to be examined further. An important step will be to test the effects of HERV neutralizing antibodies in humans.

"It should be noted that in patients with relapsing multiple sclerosis, a phase 2b clinical trial using the HERV protein neutralizing antibody, temelimab, was conducted. We are now waiting to see if the treatment has shown beneficial effects on remyelination or attenuated neurodegeneration. "