The human immune system has often been thought to play an important role in various neurological disorders, such as Amyotrophic Lateral Sclerosis (ALS) and a form of ataxia with ocular motor defects called AOA2. Now, a study from the Icahn School of Medicine at Mount Sinai has identified a vital protein often associated with these neurologic diseases, showing its role in response to viral infections.
The findings from this study were published recently in Nature Immunology through an article entitled “Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis.”
The investigators found that genetic changes to the helicase senataxin ameliorated the protein’s ability to moderate the inflammatory response to certain viral infections—a scenario that could lead to chronic persistent inflammation and aggravate underlying neurologic disorders.
“We knew this protein was important, but its precise activity and role in the antiviral response had never been demonstrated before,” stated Harm van Bakel, Ph.D., assistant professor in the department of genetics and genomic sciences at Mount Sinai and co-author on the curent study.
The Mount Sinai team knew from previous studies that patients suffering from senataxin-related forms of ALS and AOA2 had a defect in the SETX gene, which produced a dysfunctional form of the protein. Further observations lead the team to discover that senataxin was expressed to reduce the viral load as part of the immune systems’ innate response infection.
“Mechanistically, we propose a model whereby SETX attenuates the activity of RNA polymerase II at genes stimulated after a virus is sensed and thus controls the magnitude of the host response to pathogens and the biogenesis of various RNA viruses (e.g., influenza A virus and West Nile virus),” stated the researchers. “Our data indicate a potentially causal link among inborn errors in SETX, susceptibility to infection, and the development of neurologic disorders.”
Additionally, the researchers employed gene expression studies and chromatin analysis in an attempt to uncover the regulatory role of the senataxin protein. While previous work to characterize senataxin has been conducted in yeast cells, this study obtained new information by analyzing human cells and animal models. The team found that senataxin has a much greater influence in regulating gene activity than was previously known.
“This is a protein implicated in neurodegenerative disease that has now been linked to our innate antiviral mechanism, and it offers an intriguing clue to a relation between the inflammatory response and these diseases,” said Ivan Marazzi, Ph.D., assistant professor of microbiology at Mount Sinai and senior author on the study. “Whether viral infection plays a role in disease progression remains to be seen, but this discovery has broad implications for biomedical research and opens up new avenues that we look forward to pursuing.”