What links neurological conditions and ancient viruses?
Transposable elements, which scientists also call transposons or jumping genes, are stretches of DNA that harbor the ability to move around our genome.
Scientists can trace back one type of transposon — human endogenous retroviruses (HERVs) — to ancient retroviruses that inserted themselves into the human genome millions of years ago. HERVs make up about 8% of our DNA.
Some HERVs hold crucial functions during processes such as embryonic development. But most HERVs lie dormant, silenced by DNA modifications.
Yet, in a recent review article in Frontiers in Genetics, researchers from Heinrich Heine University in Dusseldorf, Germany, detail how some HERVs may be reactivated and wreak havoc in our brain and central nervous system.
HERVs in neurological diseases
Back in 1989, Hervé Perron, then at the University of Grenoble in France, was the first to identify the presence of viral particles in cell cultures isolated from the cerebrospinal fluid (CSF) of a person with multiple sclerosis (MS). He later discovered that these originated from a transposon called HERV-W.
Activation of this dormant HERV results in an immune reaction. HERV-W envelope (ENV) RNA and protein are present at increasing levels in the serum and CFS of people with MS, but only rarely in those without the condition.
"Linking this HERV reactivation to autoimmune attacks in MS, it was found that HERV proteins can trigger an immune response against myelin, which triggers MS-like disease in mouse models," explains Patrick Kuery, a professor of neurodegeneration and senior review author.
Research also suggests that immune system mediators and environmental factors, such as diet and drugs, can switch HERVs back on, although there is limited evidence at this point.
MS is not the only neurological disease where scientists suspect HERV involvement. A number of studies have implicated reactivation of HERV-K in amyotrophic lateral sclerosis (ALS), a form of motor neuron disease.
When it comes to schizophrenia, the case is less clear.
"HERV proteins have been reported to increase expression of schizophrenia-linked genes in cultured human brain cells," explains Kuery. "However, studies on schizophrenia [patients] show inconsistent changes in HERV expression in blood, CSF, and postmortem brain tissue compared to healthy controls."
Can deactivating HERV improve MS?
In MS, the immune system attacks myelin, the protective layer that coats many neurons in the central nervous system.
Repairing this myelin damage by allowing the cells in the CNS to remyelinate neurons may prove an effective strategy to treat MS.
Since identifying HERV-W in MS patients, Perron co-founded the pharmaceutical company GeNeuro and developed a monoclonal antibody called GNbAC1 that targets the HERV-W ENV protein. Scientists are currently testing the antibody in clinical trials.
In a recent paper published in Proceedings of the National Academy of Sciences of the United States, Kuery, Perron, and colleagues dug deeper into the mechanism that links HERV-W to MS.
The team found cells that contained the HERV-W ENV protein in close proximity to neurons in brain tissue of MS patients, particularly in areas that contained chronic and acute MS lesions.
Dr. Tobias Derfuss, a professor in clinical neuroimmunology at the University of Basel in Switzerland, was a principal investigator of one of the clinical trials investigating the use of GNbAC1 in MS and a member of the steering committee for a further trial.
Writing in Therapeutic Advances in Neurological Disorders, Dr. Derfuss comments: "This treatment approach of GNbAC1 and the concept of a HERV-associated pathophysiology in MS remain controversial."
He explains that the results of the clinical trials investigating GNbAC1 for the treatment of MS indicate that the antibody does not prevent the immune system from attacking myelin, meaning it does not prevent MS.
The antibody may, on the other hand, kickstart remyelination.
"Pharmacodynamic and imaging data do not reveal any immunomodulatory effects of GNbAC1. MRI changes during a phase IIb study with GNbAC1 are compatible with remyelination."
Dr. Tobias Derfuss
MS is a complex disease, and scientists do not fully understand the biology of HERVs. A HERV-modifying therapeutic may prove to be a promising treatment for people living with MS, but its true potential remains to be seen.