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Sep 14, 2007

Investigators Identify Proteins Involved in an Inherited Form of ALS

  • University of Iowa (UI) researchers say that two cell-signaling proteins called Nox1 and Nox2 appear to play a role in disease progression of an inherited form of ALS.

    Nox proteins generate reactive oxygen species (ROS). ROS are essential for normal cell functions including signaling. An excess, however, can cause oxidative stress, which contributes to cell damage and death in neurological diseases.

    While studying Nox genes and ROS signaling, the UI team discovered that superoxide dismutase-1 (SOD-1), a protein that is mutated in an inherited dominant form of ALS, interacts with specific structures in cells that regulate ROS production by Nox proteins.

    This finding suggested that Nox proteins might be involved in the damaging disease processes at work in ALS, the scientists explain. They thus decided to examine the effect of removing Nox proteins in mice that have the ALS-causing SOD-1 mutation.

    Deleting either Nox1 or Nox2 genes from mice with the inherited type of ALS significantly increased the lifespan of the mice, according to the investigators. Nox2 deletion reportedly produced the most dramatic effect, nearly doubling the lifespan of the mice. In addition, Nox2 deletion increased the time from disease onset to death, they add.

    In addition, the UI study also showed that even a 50% reduction in Nox2 activity can significantly delay the onset of motor neuron disease.

    This research suggests that mutations in SOD-1 result in hyperactive inflammatory responses in the spinal cord and brain. Excessive ROS production by Nox proteins in these hyperactive immune cells appear to be a cause of cellular destruction and loss of motor neurons.

    “These ROS signaling pathways and specifically dysregulation of the pathways might be a component of many types of neurodegenerative diseases,” points out John Engelhardt, Ph.D., professor and head of anatomy and cell biology in the UI Roy J. and Lucille A. Carver College of Medicine. “This means that drugs that might treat ALS by knocking down these pathways might also be beneficial for Alzheimer's and Parkinson's disease.”

    The UI team’s work was published online on September 13 in the Journal of Clinical Investigation.



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