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Study Identifies Promising New Targets for Alzheimer's, Parkinson's

by VR Sreeraman on January 8, 2012 at 12:33 PM
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 Study Identifies Promising New Targets for Alzheimer's, Parkinson's

Two related studies offer hope of new targets for diseases such as Alzheimer's and Parkinson's.

The studies have identified promising genes and small molecules to use against diseases of protein folding, such as Alzheimer's, Parkinson's and Huntington's diseases, amyotrophic lateral sclerosis (ALS), cancer, cystic fibrosis and type 2 diabetes.

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More than 300 diseases have at their root proteins that misfold, aggregate and eventually cause cellular dysfunction and death.

The new Northwestern University research 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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The first genetic study 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 led by Richard I. Morimoto, the researchers 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.

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 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. Figuring out how nine genes-as opposed to 150 -- work is a manageable task," Morimoto said.

In another 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 studies have been published by the journal PLoS Genetics and the journal Nature Chemical Biology.

Source: ANI
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