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Lorie

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01/25/08 Unexpected Discovery
Provides New Lead in ALS


Investigators at the University of Iowa led by molecular biologist John Engelhardt say they’ve uncovered an unexpected protein-protein interaction that appears to open a new avenue in the study of amyotrophic lateral sclerosis (ALS). Their results were published online yesterday in the Journal of Clinical Investigation.

Engelhardt and colleagues found that a protein called SOD1 normally interacts with the protein Rac1. The SOD1-Rac1 complex then triggers a third protein, called Nox2, to produce potentially dangerous molecules called reactive oxygen species, or ROS. (The connection between Nox2 and ROS production was already known.)

ROS are highly reactive molecules that are needed for normal functioning of cells. However, in excess, they can cause a type of cell damage known as oxidative stress, which is known to occur in ALS, and inflammation, which has also been implicated in this disease.


“ALS is a devastating disease that paralyzes and kills people in the prime of their lives,” said Valerie Cwik, MDA’s medical director and vice president of Research. “MDA is dedicated to leaving no stone unturned in the search for effective treatments, and we plan to follow up on this lead immediately.”

A mutation in the gene for SOD1 is the cause of an inherited form of ALS in some 1 percent to 3 percent of people with the disease. Most ALS cases are not directly inherited (although genetic factors contribute to disease susceptibility), and their cause is so far unknown. Mice with mutated SOD1 genes have been used for several years to study ALS.

“When SOD1 binds to Rac1, the Nox2 protein produces ROS,” Engelhardt explained. “However, [normally] as soon as there is an excess of ROS (hydrogen peroxide), SOD1 separates from Rac1 and the Nox2 complex stops producing ROS. In essence, SOD1 acts like a thermostat, which senses ROS and tells the Nox2 complex when to stop producing ROS.”

In contrast, when the SOD1 gene is mutated, it leads to production of an abnormal SOD1 protein, which is apparently not sufficiently sensitive to ROS levels and doesn’t disengage from Rac1 as they rise.

“With the thermostat broken, mutant SOD1 keeps the ROS-producing furnace burning in the cell,” Engelhardt said.

The new finding is the first to directly connect mutated SOD1 genes with the overproduction of toxic levels of ROS molecules and, therefore, with oxidative stress and inflammation.


Posted by Lorie:-D
 

Vicki S

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Thanks Lorie for posting this. It gives us a little hope to hang on to.

Vicki:-D
 

Lorie

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We have to hang on

We have to hang on. If we didn't have "Hope" & "Faith". What else would matter?

We shall not give up!

Lorie:-D
 

pmbenb83

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Lorie,
Thanks so much for keeping us in the loop. What exciting news!

My husband tested negative for the SOD1. Down the road, would this be of benefit to a person with sporadic ALS? It is definitely a huge step in the right direction! :)

Thanks again!
Pam B in Va
 
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