Researchers Find a Link Between Neurodegenerative Disease and the Body’s Response to Viral Infections

A study published in the latest edition of Nature Immunology presents evidence that a key protein associated with Amyotrophic lateral sclerosis (ALS) also plays an important role in a patient’s immune response to viral infections.  The study entitled, “Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis,” was conducted by researchers at the Icahn School of Medicine, Mount Sinai, NY, and a team of international collaborators from Singapore, Canada, and Australia.

Background Terminology:

• Helicase: Class of enzymes that are essential during DNA replication because they separate double-stranded DNA into single strands allowing each strand to be copied.
• Allele: An allele is one of two or more versions of a gene. An individual inherits two alleles for each gene, one from each parent.
• Wild-type: Encoded by the most common allele in a particular natural population is known as the wild type- for example a penguin with a tuxedo type coloring is the wild-type versus an albino penguin that takes the mutant form in the population.
• Transcription: Transcription is the process by which the information in DNA is copied into messenger RNA (mRNA) for protein production.

Sentataxin is a type of helicase that is produced in a wide range of tissues, such as the he brain, spinal cord, and muscles.  Studies have shown that mutations in the senataxin gene (SETX) are known to cause certain types of neurodegenerative disorders such as ALS and ataxia with oculomotor apraxia type 2 (AOA2). Currently, the reasons why these mutations result in neurodegenerative diseases are not understood.

In a University press release, Dr. Matthew Miller, PhD, Assistant Professor in the Department of Biochemistry and Biomedical Sciences, and Investigator at the Michael G. DeGroote Institute for Infectious Diseases Research at McMaster University explains the study, stating, “We have found that senataxin deficiency, and cells from individuals with these neurodegenerative diseases, respond abnormally to viral infections. Specifically, they generate abnormally high amounts of inflammation, which is known to play an important role in several neurological diseases. Our study identifies abnormal inflammation as a potential contributing factor in ALS, which opens the door to explore new therapeutic options.”

Study Methods

The researchers identified this abnormal inflammation by utilizing gene expression studies as well as in-depth DNA analysis to uncover the regulatory role of the helicase in yeast cells, animal models and human wild-type cells that had undergone depletion of SETX and SETX-deficient cells derived from patients with AOA2. The findings showed that SETX-deficient cells derived from patients with AOA2 had higher expression of antiviral mediators in response to infection than did wild-type cells. Also, they found that senataxin has far more power to regulate gene activity than was previously known.

In a press release about the findings, Dr. Honoratus Van Bakel, PhD MS, Assistant Professor,  Department of Genetics and Genomic Sciences, Icahn Institute of Genomics and Multiscale Biology, Mount Sinai, and co-author of the study, stated: “We knew this protein was important, but its precise activity and role in the antiviral response had never been demonstrated before. Teasing out the function of senataxin required an interdisciplinary approach that would not have been possible without international and cross-department collaboration and the advanced technology resources available at Mount Sinai.”

The sentiment was shared by, Dr. Ivan Marazzi, PhD, Assistant Professor in Microbiology at Mount Sinai, and co-author of the study, “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. 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.”