But what actually happens when the epigenetic brakes are released by environmental factors and the genome of retroviruses wakes up from its slumber? A study carried out in 2021 by a team led by neurogeneticist Johan Jakobsson from the Swedish University of Lund gives an idea of this. The researchers focused on the Trim28 protein, an epigenetic switch that suppresses the expression of endogenous retroviruses. Using the CRISPR/Cas9 gene scissors, they switched off the protein in the neural progenitor cells of mice during brain development. They then found many expressed endogenous retroviruses in the adult brain. This was accompanied by a strong activation of the microglia, the immune cells of the brain. They usually patrol the site and make sure everything is ok. However, they can also become aggressive and attack other cells.
Endogenous retroviruses prime the immune system
That fits in well: For some years now, scientists have been assuming that neurological and psychiatric diseases are at least partly triggered by an overreaction of the immune system. This becomes particularly clear in the case of multiple sclerosis, in which the patient’s own immune system attacks and damages nerve cells. Even if it is possible to prevent individual outbreaks of the disease with medication, nerve cells are constantly degenerating in the background. The microglial cells play a role in this. Patrick Küry and his colleagues were able to show that activation by human endogenous retroviruses can lead to a more aggressive type of microglia in MS patients. The immune cells are also altered in mental illnesses such as schizophrenia and get out of control. “So this could be a general mechanism,” Küry suspects. “When the microglial cells are stimulated by the retroviruses, they become aggressive.” This can lead to the development of a neurological or psychological disorder over a long period of time.
»When microglial cells are stimulated by retroviruses, they become aggressive«(Patrick Kury)
The same goes for autism spectrum disorders. In a 2019 study, the molecular biologist Emanuela Balestrieri from the University of Tor Vergata in Rome not only found increased expression of retrovirus genes in the blood of autistic children and their mothers. She also encountered increased levels of cytokines, pro-inflammatory immune messengers. Another proof that there is probably a connection between retroviruses and an overactive immune system.
Fateful Neighborhood
In this way, the viruses could also negatively affect the development of the brain. A group led by neuroscientist Laurent Groc from the University of Bordeaux found evidence for this. She introduced genes from human endogenous retroviruses into hippocampal cells in rats. To do this, the researchers use a process called electroporation, in which cell membranes are temporarily made permeable. Expression of the retroviral genes activated the immune system, namely microglial cells and cytokines. This ultimately disrupted the development of certain synapses in the hippocampus, which play a crucial role in the formation of memories. As a result, the rodents developed behavioral deficits: they showed a weaker filter function in the face of startle stimuli such as loud noises – a phenomenon that is also observed in people with schizophrenia. If you play a loud tone to test persons, they show a startle reaction. But if this startle stimulus is preceded by a soft tone (prepulse), it weakens (inhibits) itself. This prepulse inhibition reflects the filter function of the brain, which distinguishes important from unimportant stimuli. In people with schizophrenia, this filtering function is impaired.