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Study links normal function of protein, not its build up inside cells, to death of neurons
Date:9/22/2010

he genome, but problems arise when they occur too frequently. That is what happens in the estimated 1 in 50,000 males with SBMA.

In the case of SBMA, the repeated sequence occurs in the gene for the androgen receptor. The repeated nucleotide sequence CAG is protein-production shorthand for an amino acid called glutamine. The resulting androgen receptor (AR) protein includes surplus glutamine.

After earlier work by other investigators showed that blocking testosterone prevented male mice with the SBMA mutation from developing the disease, Taylor and his colleagues set out to track what happened inside cells after the hormone bound to the mutated AR protein.

Working in a Drosophila fruit fly model of the disease, the scientists identified a small region of the AR protein, known as the AF-2 domain, which played a pivotal role.

Using a variety of techniques, researchers demonstrated they could rescue the cells by preventing certain members of a family of proteins called coregulators from binding to the AF-2 domain. Coregulators partner with AR and other transcription factors to regulate gene expression.

"In this study, we showed the ability of the mutant protein to interact with the normal binding partners is an essential step in the cascade of degeneration. By blocking it, we block degeneration," Taylor said. He added that the AF-2 domain is far from the mutated region of the AR protein. "That would be unexpected if the mechanism of toxicity were related to the protein aggregating," he explained.

Meanwhile, investigators are still studying why the protein's change in function is so deadly to cells. Taylor noted that research into inherited diseases like SBMA has historically provided important clues into the mechanisms at work in other more common neurodegenerative disorders, including Alzheimer's.

The findings also hold hope that treating or preventing SBMA by selectively disrupting AF-2 binding will so
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Contact: Summer Freeman
summer.freeman@stjude.org
901-595-3061
St. Jude Children's Research Hospital
Source:Eurekalert

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