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Gene newly linked to inherited ALS may also play role in common dementia
Date:2/20/2008

n called superoxide dismutase-1 (SOD1). Since then, many had thought altering the SOD1 gene's function was the most promising way to model and understand sporadic ALS.

"That has all been turned upside down in the last two years, though," says Cairns. "In that time, abnormal TDP-43 deposits have been identified in sporadic ALS cases and in some inherited forms of ALS that don't involve a SOD1 mutation."

TDP-43 is an influential regulator of messenger RNA splicing, the process that edits protein-building instructions from DNA to allow the proteins to be built properly. TDP-43 abnormalities in ALS patients have included altered folding and a chemical change known as phosphorylation, both of which can radically alter the protein's function.

As a result, several research groups have been looking for a case where a mutation in the TDP-43 gene was linked to inherited disease. The new study is the first to tentatively establish such a link. Michael Gitcho, Ph.D., a postdoctoral research associate in Dr. Cairns' lab, and colleagues found that every member of a family affected by an inherited form of ALS had a particular mutation in TDP-43. Next, they looked at 1,505 people not related to the family and unaffected by ALS. This second search found no examples of the same mutation.

Because the family they studied is small, scientists need further evidence to confirm that the mutation is causing ALS. Researchers are working to introduce the mutated human TDP-43 gene they identified in the family into a transgenic mouse model. They hope the mouse will generate a model for ALS-like pathology.

If this affirms the link, they will begin tracing the effects of the mutation on genes whose splicing is regulated by TDP-43, working to identify key links in the chain reaction that leads to motor neuron death. These links may become new targets for pharmaceutical treatments.

What they learn may also shed light on other neurodegenerative
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Contact: Michael C. Purdy
purdym@wustl.edu
314-286-0122
Washington University in St. Louis
Source:Eurekalert

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