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Genes That Improve Survival in Mice With ALSU , Identified by Iowa Team

by Medindia Content Team on  September 17, 2007 at 7:11 PM Genetics & Stem Cells News   - G J E 4
Genes That Improve Survival in Mice With ALSU , Identified by Iowa Team
The UI team, led by John Engelhardt, Ph.D., professor and head of anatomy and cell biology in the UI Roy J. and Lucille A. Carver College of Medicine, discovered that two cell-signaling proteins called Nox1 and Nox2 appear to play an important role in disease progression of an inherited form of ALS. This work is published in the Sept. 13 issue of the Journal of Clinical Investigation.
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Deleting either Nox1 or Nox2 genes from mice with the inherited type of ALS significantly increased the lifespan of the mice. Nox2 deletion produces the most dramatic effect, nearly doubling the lifespan of the mice. In addition, Nox2 deletion dramatically increased the survival index -- the time from disease onset to death. This is the first report of a single gene that affects the survival index in ALS models.

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"The findings provide encouraging data that there are new potential therapeutic targets in ALS," said Engelhardt, who also is the Roy J. Carver Chair in Molecular Medicine. "Whether our findings will bear out in humans still has to be evaluated, but our results suggest that inhibiting Nox proteins might significantly enhance survival in ALS."

Nox proteins generate reactive oxygen species (ROS) -- short-lived, highly reactive molecules. ROS are essential for normal cell functions including signaling, but excess ROS can cause damaging 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 unexpected finding suggested that Nox proteins might be involved in the damaging disease processes at work in ALS, and prompted the UI team to examine the effect of removing Nox proteins in mice that have the ALS-causing SOD-1 mutation.

In addition to finding that deletion of the Nox genes delays disease onset and enhances survival in the ALS mice, the UI study also shows that even a 50 percent reduction in Nox2 activity can significantly delay the onset of motor neuron disease. This means a drug that only partially inhibits the Nox protein might still provide a therapeutic benefit.

The UI study suggests that mutations in SOD-1 responsible for certain forms of ALS 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 significant cause of cellular destruction and loss of motor neurons. Inflammation and oxidative stress are thought to play an important role in other neurodegenerative diseases besides ALS.

"These ROS signaling pathways, and specifically dysregulation of the pathways, might be a component of many types of neurodegenerative diseases," Engelhardt said. "Which means that drugs that might treat ALS by knocking down these pathways might also be beneficial for Alzheimer's and Parkinson's disease."

The research team now plans to look for drugs that inhibit activation of Nox1 and Nox2. They also will investigate how the SOD-1 mutation leads to hyperactivation of Nox proteins.

"The closer we get to clarifying the basic mechanism of how the ALS mutations in SOD-1 lead to hyperactivation of inflammatory Nox proteins, the easier it will be to identify drugs that will interfere with that process," Engelhardt added.

Source: Eurekalert
SPH/J
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