Protein Folding Protection Prevents Alzheimer's & Huntington's
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EmailIn brain cells, proteins start their work by folding themselves into the proper shape. What that means is illustrated in the video to the right. (Check out the Folding@Home Project described in the video for more on how you can contribute some of your computer's spare power to help find new brain disease treatments.)
If proteins in the brain misfold, Alzheimer's, Parkinson's or Huntington's disease may result. Two Northwestern University studies offer strategies for tackling protein misfolding.
The new Northwestern research fights protein misfolding in two ways:
- It identifies new genes and pathways that prevent protein misfolding and toxic aggregation, keeping cells healthy.
- It also identifies small molecules with therapeutic potential that restore health to damaged cells, providing new targets for drug development.
See the "More Information" section below for links to the studies.
Richard I. Morimoto led the research. He is the Bill and Gayle Cook Professor of Biology in the department of molecular biosciences and the Rice Institute for Biomedical Research in Northwestern’s Weinberg College of Arts and Sciences. He also is a scientific director of the Chicago Biomedical Consortium.
Dr. Morimoto said,
“These discoveries are exciting because we have identified genes that keep us healthy and small molecules that keep us healthy. Future research should explain how these two important areas interact.”
New Genes
The transparent roundworm C. elegans, was the subject of this genetic study. This roundworm was chosen because it shares much of the same biology with humans. In addition, its genome, or complete genetic sequence, is well-studied.
In this study, Professor Morimoto's team tested all 19,000 genes in C. elegans. They reduced expression of each gene one at a time. They then checked to see if the gene suppressed protein aggregation in the cell, increased it or left it unaffected.
150 genes showed an effect. Zooming in by conducting further tests, the researchers zeroed in on nine genes that made all proteins in the cell healthier. The nine genes made up a core homeostastis network, protecting the animal’s proteome (the organism's complete set of proteins). Professor Morimoto remarked,
“These are the most important genes. Figuring out how nine genes -- as opposed to 150 -- work is a manageable task.”
New Small Molecules
In the Nature Chemical Biology study, Morimoto and his colleagues screened nearly 1,000,000 small molecules in human tissue culture cells. They then identified the small molecules that restore the cell’s ability to protect itself from protein damage.
Proper Protein Folding
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.
The researchers found that the proteostasis regulators restored the health of the cell. They also brought about a reduction of protein aggregation and protection against misfolding. As a result, diseased animals saw health restored when 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. Professor Morimoto concluded that,
“We don’t yet know the detailed mechanisms of these small molecules, but we have identified some good drug targets for further development."
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More Information
The genetic screening study is published by the journal PLoS Genetics. The small molecule study is published by the journal Nature Chemical Biology.
The PLoS Genetics paper is titled “A Genetic Screening Strategy Identifies Novel Regulators of the Proteostasis Network.” M. Catarina Silva, a joint-doctoral student at Northwestern in the Morimoto lab and the University of Lisbon is the first author. TheNational Institutes of Health, the Huntington’s Disease Society of America Coalition for the Cure and the Daniel F. and Ada L. Rice Foundation supported the research.
The Nature Chemical Biology paper is titled “Small-Molecule Proteostasis Regulators for Protein Conformational Diseases.” Barbara Calamini, a former postdoctoral fellow at Northwestern who is now a research scientist at Duke University, is the first author. The National Institutes of Health and the Daniel F. and Ada L. Rice Foundation supported the research.
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