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Tiny worm points to big promise
Date:1/6/2012

xpression of each gene one at a time and looked to see if the gene suppressed protein aggregation in the cell. Did the gene increase aggregation or lessen it or have no effect at all?

The researchers found 150 genes that did have an effect. They then conducted a series of tests and zeroed in on nine genes that made all proteins in the cell healthier. (These genes had a positive effect on a number of different proteins associated with different diseases.)

These nine genes define a core homeostastis network that protects the animal's proteome (the entire set of proteins expressed by the organism) from protein damage. "These are the most important genes," Morimoto said. "Figuring out how nine genes -- as opposed to 150 -- work is a manageable task."

In the Nature Chemical Biology study, Morimoto and his colleagues screened nearly one million small molecules in human tissue culture cells to identify those that restore the cell's ability to protect itself from protein damage.

They identified seven classes of compounds (based on chemical structure) that all enhance the cell's ability to make more protective molecular chaperones, which restore proper protein folding. The researchers call these compounds proteostasis regulators. They found that the compounds restored the health of the cell and resulted in reduction of protein aggregation and protection against misfolding. Consequently, health was restored when diseased animals were treated with the small molecules.

Morimoto and his team then conducted detailed molecular analyses of 30 promising small molecules, representing all seven classes. They discovered some compounds were much more effective than others.

"We don't yet know the detailed mechanisms of these small molecules, but we have identified some good drug targets for further development," Morimoto said.

The PLoS Genetics paper, titled "A Genetic Screening Strategy Identifies Novel Regulators of the Pro
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Contact: Megan Fellman
fellman@northwestern.edu
847-491-3115
Northwestern University
Source:Eurekalert

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