Up to 40% of the human genome are retrotransposons. Among these are sequences that are not dissimilar to retroviral particles like the endogenous retroviruses (ERV). Their potential role in the development of dementia has recently been the focus of a new study in a mouse model.
Many Endogenous Retroviruses (ERVs) became part of our DNA millions of years ago. Up to now, these sequences have been regarded as meaningless for the most part in the process of human evolution, and also, determined as unimportant in the DNA of, for example, mice. However, in recent years, there has been an increasing amount of researchers supporting the notion that ERVs may well have a role to play in health and disease.
In a recent paper, researchers showed that chronically activated ERVs in the brain are associated with cognitive impairment, among other things. To determine this, the scientists used hippocampus reactions in a mouse model. In particular, the mice were found to have limitations that could no longer produce mitochondrial antiviral signaling protein (MAVS).
It has been known for quite some time that ERV transcription can be found in the brains of both humans and mice and that such reactivation of retrotransposons is closely related to autoimmune reactions and neurodegenerative diseases.
Generally speaking, retrotransposons are an example of "evolution at play". If every section of an organism's DNA were necessary for its survival, every random mutation would end in a catastrophe. On the other hand, retrotransposons, and the endogenous retroviruses underneath them, offer our DNA the genetic breadth to "try out" something new. But what is the consequence should this "ancient DNA" suddenly become active again?
Normally, humans and animals control the activity of retrotransposons via a variety of mechanisms, the best known of which are DNA methylation, DNase activity, immunoglobulins or certain signal proteins. If these control mechanisms are disrupted, the retrotransposon sequences are reactivated, which can increase the risk of morbidity and even mortality from autoimmune reactions and malignant tumors.
Thus, free retroviral RNA genome strands suddenly reappear in the cells, which are recognized by the cell's own immune receptors (toll-like receptors, a.k.a. TLRs, or mitochondrial antiviral signaling protein, a.k.a. MAVS) and trigger an inflammatory process through their activation.
In the case of degenerative diseases in the brain, studies have shown that both acute and chronic inflammatory reactions lead to cell damage and thus to loss of cognitive functions. In the mouse experiment, the mice with endogenous retroviral "reexpression" developed deficits in anxiety perception and also in spatial environmental learning, confirming the loss of cognitive functions.
Original source:
Sankowski R et al., Endogenous retroviruses are associated with hippocampus-based memory impairment. PNAS 2019; pnas.org/content/pnas/early/2019/11/27/1822164116.full.pdf