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Link Between ALS and Abnormal Immune Response Established

A key protein previously implicated in Lou Gehrig’s disease and other neurological diseases plays an important role in the response to viral infection, according to a study led by scientists from the Icahn School of Medicine at Mount Sinai published today in Nature Immunology.

Neurological diseases have long been associated with inflammation, part of the body’s response to injury or infection that occurs when immune cells home in to attack invaders like bacteria and viruses, and to drive healing, but the link between them has not been understood.

This new study result suggests that genetic changes take away the ability of a protein called senataxin to moderate the inflammatory response to certain viral infections, possibly leading to persistent inflammation that could aggravate disease progression.

Using cutting-edge genomic tools, the scientists found that senataxin is deployed to quench the body’s natural antiviral response at a specific point; without such control, prolonged exposure to the antiviral response can lead to inflammation. People with senataxin-related forms of ALS and ataxia have a defective SETX gene that leads to a dysfunctional form of the protein.

“We knew this protein was important, but its precise activity and role in the antiviral response had never been demonstrated before,” said Harm van Bakel, co-author of the paper and Assistant Professor in the Department of Genetics and Genomic Sciences and in the Icahn Institute of Genomics and Multiscale Biology at Mount Sinai. “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.”

This shows the outline of a person's head.

Among the study’s key findings was that learning motor tasks such as running forward and backward induced completely separate patterns of lightning bolt-like activity in the dendrites of brain cells. The image is for illustrative purposes only. Image credit: NIH.

Scientists used gene expression studies as well as in-depth chromatin analysis to uncover the regulatory role of the protein. While most work to characterize the protein has been conducted in yeast cells, this project gained new information by analyzing human cells and animal models. The team found that senataxin has far more power to regulate 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, co-author of the paper and Assistant Professor in Microbiology at Mount Sinai. “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.”

About this ALS research

Funding support for the study, which took four years to complete, was provided by National Institutes of Health grants RO1 NS047325 and P01 NS074972.

Contact: Glenn Farrell – Mount Sinai School of Medicine
Source: Mount Sinai School of Medicine press release
Image Source: The image is credited to NIH and is in the public domain
Original Research: Abstract for “Senataxin suppresses the antiviral transcriptional response and controls viral biogenesis” by Matthew S Miller, Alexander Rialdi, Jessica Sook Yuin Ho, Micah Tilove, Luis Martinez-Gil, Natasha P Moshkina, Zuleyma Peralta, Justine Noel, Camilla Melegari, Ana M Maestre, Panagiotis Mitsopoulos, JoaquĆ­n Madrenas, Sven Heinz, Chris Benner, John A T Young, Alicia R Feagins, Christopher F Basler, Ana Fernandez-Sesma, Olivier J Becherel, Martin F Lavin, Harm van Bakel and Ivan Marazzi in Nature Immunology. Published online March 30 2015 doi:10.1038/ni.3132

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