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By stopping misfolds, genes keep us healthy

NORTHWESTERN (US) — Researchers have identified a set of genes that prevent protein misfolding, a condition linked to a range of disorders, including Alzheimer’s and cancer.

To do its job within the cell, a protein must first fold itself into the proper shape. If it doesn’t, trouble can result—more than 300 diseases have at their root proteins that misfold, aggregate, and eventually cause cellular dysfunction and death.

The new research, reported in two studies, identifies new genes and pathways that prevent protein misfolding and toxic aggregation, keeping cells healthy, and also identifies small molecules with therapeutic potential that restore health to damaged cells, providing new targets for drug development.

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“These discoveries are exciting because we have identified genes that keep us healthy and small molecules that keep us healthy,” says Richard Morimoto, professor of biology at Northwestern University, who led the research. “Future research should explain how these two important areas interact.”

The genetic study, reported in PLoS Genetics was conducted in the transparent roundworm C. elegans, which shares much of the same biology with humans. The small animal is a valued research tool because of this and also because its genome, or complete genetic sequence, is known.

In the work, Morimoto and his team tested all of the approximately 19,000 genes in C. elegans. They reduced expression 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, 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 says. “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.

Detailed molecular analyses of 30 promising small molecules were then conducted, representing all seven classes. Some compounds were much more effective than others, Morimoto says.

“We don’t yet know the detailed mechanisms of these small molecules, but we have identified some good drug targets for further development.”

The studies were funded by the National Institutes of Health, the Huntington’s Disease of America Coalition for the Cure, and the Daniel F. and Ada L. Rice Foundation.

Barbara Calamini, a former postdoctoral fellow at Northwestern who is now a research scientist at Duke University, is the first author of the Nature Chemical Biology paper.

More news from Northwestern University: www.northwestern.edu/newscenter/index.html

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