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Jan 25, 2008

Scientists Discover Novel Role of Mutated Protein in ALS

  • Discovery of an unexpected protein-protein interaction has led researchers to identify a compound that slows the progression of amyotrophic lateral sclerosis (ALS) in mice and nearly doubles the animals’ lifespan.

    While studying the basic biology of cell signaling, scientists found that superoxide dismutase-1 (SOD1), a protein that is mutated in inherited forms of ALS, interacts with Rac1, a protein that regulates the production of reactive oxygen species (ROS) by the Nox2 protein complex.

    Abnormal ROS production has been implicated as a cause of ALS and other neurodegenerative diseases. ROS are short-lived, highly reactive molecules that are essential for normal cell functions including signaling. Excess ROS, however, can cause damaging oxidative stress.

    Using a series of experiments in cells and in mice, the researchers explored the interaction between SOD1 and Rac1. “When SOD1 binds to Rac1, the Nox2 protein produces ROS,” explains study leader, John Engelhardt, Ph.D., professor and head of anatomy and cell biology in the University of Iowa Carver College of Medicine.

    “However, as soon as there is an excess of ROS (hydrogen peroxide), SOD1 separates from Rac1, and the Nox2 complex stops producing ROS. In contrast, the mutant version of SOD1, which causes ALS, is not as sensitive to ROS and doesn’t disengage from Rac1.”

    The investigators also found that deletion of the Nox2 protein almost doubles the lifespan of mice with an inherited form of ALS. This strengthens the notion that Nox2-generated ROS plays a role in ALS progression, the researchers say. Furthermore, they showed that apocynin, which blocks Nox2, slows progression and increases lifespan of ALS-affected mice.

    Scientists at the University of Iowa and University of Kansas conducted this research. The study was published January 24 online in the Journal of Clinical Investigation.


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