 "Photo: Nafis Azad/Collegian")
In hopes of wiping out some of the world's deadliest diseases, one University of Massachusetts professor recently published an article to shed some light on possible solutions.
UMass professor of chemistry, Lila Gierasch, has recently published an article along with her co-author Zoya Ignatova of the Max Planck Institute in Martinsried, Germany outlining their recent work on the anti-protein clumping capabilities of the molecule known as proline.
This research has ramifications in both the biotechnology and health care industries. The most lauded aspect of the study is that it is viewed as a preliminary step towards preventing and understanding many complex diseases such as Alzheimer's, Huntington's and Parkinson's, which are all believed to be linked in some way to protein clumping, or aggregation as it is more often called.
However Gierasch points out that her studies thus far are in bacterial cells, "it is far from clinical studies" she said, emphasizing the fact that "anti-Alzheimer's" drugs will not been seen on the market as a result of this work any time soon.
"This tells us something about how cells may cope with the problem of protein aggregation - that is a clinical problem in these disease" said Gierasch. "The diseases themselves are very complicated, people don't even know if the aggregates are toxic."
Therefore, she said, using proline to prevent aggregation may not cure the disease.
Proline is a small amino acid and at the center of the research. Amino acids are the building blocks of proteins which in turn are the building blocks of all cells. Therefore proline is already present in the human body, but it does not serve as a defense against clumping.
During the folding process, proteins sometimes misfold and then they tend to aggregate, or clump together and this can lead to health issues. It is also known that the longer a protein takes to fold the greater the chance that aggregates will form.
The protein used in the study was produced by bacteria cells and was intentionally given a DNA mutation that causes the protein to fold in about three seconds, as oppose to one second, thus resulting in a much higher chance of aggregation.
It was found by Gierasch and co-author Ignatova that proline, if present at the start of the folding process, will help stabilize the folded protein.
One of the keys to the study is that proline will dissolve partial folded proteins that are usually not soluble in water, a trait that often leads to aggregation. In the same way that dish-soap causes grease from a dirty pan to dissolve in water, proline helps a protein's grease-like building blocks to dissolve.
Proline is a preventative measure, not a remedy to protein aggregation. It was shown that if proline was added to a cell which already had aggregates of misfolded proteins, the proteins would not refold properly and it actually helped to stabilize the aggregate.
Besides the possible medicinal applications of proline the "very practical and very immediate [application] is in the pharmaceutical industry," said Gierasch. Pharmaceutical companies want to produce proteins for use as medicines, but they must have well folded proteins and proline is a way to improve the production of these desired proteins.
The work was done using a technique that was developed by Gierasch and Ignatova several years ago and they were able to observe the folding process "in vivo" - meaning within a living cell, as oppose to "in vitro" - inside a test tube. Using florescent dyes that were incorporated into the proteins, the folding process can be tracked along with the formation of aggregates.
The next step in the work is to continue with the same methods but manipulate the abilities of proline to stop aggregation at different stages and study the properties and morphologies of each stage. Gierasch said "this will help people who want to understand the disease, then we can see what's the toxic species - is it the early aggregate or the later?"
Associate Professor of biochemistry and molecular biology at the University of Kansas Medical Center, Mark Fisher said, "This is ground breaking… it can help us use new tools to understand how proteins fold and misfold," adding that about 50 percent of known diseases are a result of protein folding defects.
Professor Fisher has written a commentary about the research entitled "Proline to the Rescue" that will be published along with Professor Gierasch's article in the upcoming issue of the Proceedings of the National Academy of Sciences.
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