Peptide reduces aggregation of prion-like fibers
February 19, 2001
A peptide can enhance the human body's natural defenses against the formation of the amyloid fibers typical of prion-like diseases, researchers at the University of Chicago and Argonne National Laboratory show in a study published in the February 19, 2001, issue of the Journal of Cell Biology.
A new disease story is emerging from our understanding of maladies as novel as mad cow disease and as common as Alzheimer's. Proteins normally found in the body are induced to misfold and then assemble into aggregates, forming tough fibers that the body in unable to degrade. Amyloidosis is a family of diseases where these protein fibers are deposited in various organs and tissues, often resulting in organ failure and death.
One of the proteins that can cause amyloidosis is a component of antibodies, the light chain, which is naturally mutated by the immune system to meet whatever challenge might be presented by an invader.
"We had to ask why we don't all suffer from this disease," said immunologist Yair Argon, PhD, associate professor of pathology at the University of Chicago, who led the investigation. "It seems as if relatively small changes that can readily occur in the body are enough to cause amyloidosis.
"There must be mechanisms in our body to counteract their effects," he said, "and block the disastrous assembly of protein fibrils."
In the October issue of Immunity, the same researchers described how a single mutation in the region of the protein that is naturally mutated could be enough to cause one type of light chain protein to misfold and assemble into fibers.
To identify the body's defenses against these misfolded proteins, the researchers inserted into cells the gene for the misfolding-prone light chain, called SMA. As the cells produced SMA, the scientists tracked its progress, comparing it to the progress of a normal light chain inserted into other cells as a control.
Both types of light chain were successfully made by the cells. The normal light chain was properly folded and secreted from the control cells, as it should be. The SMA light chain, however, was marked by a cell molecule that targeted it for degradation, breaking it down into its component parts. Most of the misfolding-prone variant was disposed of in this way. In addition, some of the SMA also aggregated into fibers, and the cells packaged up the proteins into sacs called aggresomes.
Argon's team found that the equilibrium between these two coping mechanisms, degradation and packaging into aggresomes, is governed by another normal cell protein, called Hsp70. Hsp70 is one of a class of proteins called chaperones, that bind to unfolded proteins and prevent them from folding incorrectly. The researchers found that when extra Hsp70 was added to the cells, fewer aggresomes formed and more of the SMA was degraded.
"We think that Hsp70 is binding SMA, preventing it from aggregating, and pushing it towards the normal breakdown mechanisms in the cell," said Argon.
The researchers next created a small peptide, which they believed would bind SMA in the same way that Hsp70 does. As in the case with the addition of Hsp70, the addition of the peptide resulted in the formation of fewer aggresomes and more degradation of SMA.
"It's not practical to try to deliver whole proteins like Hsp70 as drug therapy," said Argon. "But the effectiveness of the small peptide certainly opens up the possibility of creating a rationally designed drug that enlists the body in its own defense."
Additional authors include Jeanne L. Dul, PhD, David P. Davis, PhD, and Edward K. Williamson, PhD, of the University of Chicago and Fred J. Stevens, PhD, of Argonne National Laboratory.
This work was supported by grants from the National Institutes of Health and the American Cancer Society, Illinois Division. Davies was supported in part by a National Research Service fellowship and by a Baron fellowship.
The University of Chicago Medicine
950 E. 61st Street, Third Floor
Chicago, IL 60637
Phone (773) 702-0025 Fax (773) 702-3171