A team of researchers led by the University of Helsinki report that a progressive neurodegenerative disease can be triggered by a viral infection. They discovered that a specific gene variant affecting the mitochondria disturb cellular antiviral defense responses. The results imply that viral infections can trigger and modify symptoms of neurological diseases in subjects carrying genetic sensitivity.
The findings are published in Nature in an article titled, “Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.”
“Mitochondrial dysfunction is an important contributor to pathogenesis of neurodegenerative diseases, with a considerable range of manifestations from severe epilepsy to various forms of peripheral or central nervous system degeneration,” the researchers noted.
The current study shows that deficient mitochondrial functions in immune defense are connected to the manifestation of brain diseases and sometimes also liver dysfunction. A multidisciplinary team led by academy professor Anu Suomalainen, MD, PhD, discovered that a genetic variant affecting the function of mitochondrial POLG enzyme delays detection of viral infection, leading to delayed severe inflammatory reaction.
If a subject inherits the POLG-variant from both parents, a neurological disease, MIRAS (mitochondrial recessive ataxia syndrome), manifests. However, the age of onset and manifestations of MIRAS are highly variable, raising the question of whether the disease is triggered by additional factors.
Using a variable set of model systems, the team shows that the POLG variant leads to a weakened initial immune activation in response to viral infection, followed by a delayed, overactivated inflammation damaging the brain and liver. The researchers suggest that this mechanism explains why some MIRAS patients manifest in teenagers with severe epilepsy, while some other patients with the same genetic background show disease signs years or even decades later.
“Our results indicate that external factors, such as viral infections, can modify manifestation and age-of-onset of neurological diseases,” postdoctoral scientist Yilin Kang, PhD, commented. “Identification of susceptibility factors and triggering mechanisms are valuable targets for new therapy developments. The current findings indicate the importance of new mitochondrial functions in maintaining brain health.”
