Two related studies from Northwestern University
offer new strategies for tackling the challenges of preventing and treating
diseases of protein folding.
To do its job properly within the cell, a protein first must
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 Northwestern 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.
The genetic screening study is published in PLoS Genetics.
The small molecule study is published in Nature Chemical Biology.
“These discoveries are exciting because we have
identified genes that keep us healthy and small molecules that keep us
healthy,” said Richard I. Morimoto, who led the research. “Future
research should explain how these two important areas interact.”
Morimoto 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.
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 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 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.
SOURCE – Northwestern University
Filed Under: Drug Discovery