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A fly mutation suggests a new route for tackling ALS
Date:4/8/2013

researchers discovered a mutation in the mouse, called Wlds, which enables a damaged axon to survive for weeks after injury. "That fundamentally changed how we think about an axon. Under certain circumstances, axons can survive for a much longer time than we have given them credit for," Dr. Freeman explained.

Freeman's laboratory speculated that if axon self-destruction is an active process, then there should be genes in the fly genome whose normal function is to destroy cut axons. They decided if they could break those genes responsible for axon destruction, then the axons shouldn't fall apart. To identify those genes, they performed a labor-intensive screen, randomly breaking genes in the fly genome and looking for those that when broken blocked axon destruction after injury.

This approach led to the identification of one gene, called dSarm, whose normal function is to promote the destruction of the axon after injury. "We got beautiful protection of axons when we knocked out this molecule," Dr. Freeman said. Mice and humans have forms of this gene too, and Freeman and colleagues have shown its functions in a similar way in mice. The preservation of these signaling mechanisms from flies to humans is a sign of evolutionary retention and argues for its importance.

To get closer to applying the axon death gene to the study of disease, the researchers crossed the mouse version of the Sarm mutation into a mouse model that has a type of familial ALS, which is also in humans. Although the mice still lost weight and had difficulty with a mobility test, they lived about 10 days longer than their brethren without the Sarm mutation, and at least half of their motor neurons remained intact. "Since not all the motor neurons are needed," Dr. Freeman said, "even with a 50 percent reduction a patient could feel very close to normal. It would be life-changing for the patient, so it's a step in the right direction."

"We used Wallerian dege
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Contact: Phyllis Edelman
pedelman@genetics-gsa.org
301-634-7302
Genetics Society of America
Source:Eurekalert

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