Drug Summary: Geldanamycin (GA) is a naturally-occurring drug produced by microorganisms to protect themselves from disease-causing substances. GA binds to a special kind of protein called a heat shock protein. All cells produce a common set of heat shock proteins (Hsp’s) in response to a variety of stresses, including heat, exposure to toxic compounds, or other conditions that cells normally do not experience. Experiments with bacteria, yeast, fruit flies, and mice have shown that increased production of heat shock proteins can protect an organism against stress-induced damage. There are many different kinds of heat shock proteins – each one of them performs a variety of functions that help the cell in both stressful and non-stressful conditions. Most, but not all, heat shock proteins play the role of “molecular chaperones.” Molecular chaperones are substances inside the cell that bind and stabilize proteins at intermediate stages of folding, assembly, movement across membranes, and degradation.
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How do Heat Shock Proteins work?^
How does Geldanamycin work in preventing huntingtin aggregation?^
First of all, it would be helpful to understand how GA works as an anti-tumor drug because its mode of action against cancer and huntingtin aggregation is similar. In other research, scientists have shown that GA binds to the heat shock protein Hsp 90, which acts as a molecular chaperone. Some of the proteins that Hsp 90 chaperones are proteins involved in the progression of cancer. Once GA binds to Hsp 90, Hsp 90 loses its ability to act as a chaperone. Hsp 90 is then unable to help the cancer-causing proteins fold properly, leaving them malformed. Cells in the human body continually degrade improperly folded proteins, so the end result of the loss of function of Hsp 90 is the degradation of proteins involved in the progression of cancer.
How does this mechanism help in reducing the huntingtin aggregations in HD cells? In addition to its role in directing the folding of proteins involved in cancer, Hsp 90 also associates with another protein called HSF-1 (Heat Shock Factor 1). When GA is absent in cells, Hsp 90 and HSF 1 commonly bind together and perform various functions as a unit. When GA is added to cells, it binds to Hsp 90, making Hsp 90 unable to associate with HSF 1. The free HSF 1 is then able to enter the cell nucleus where it initiates the production of other heat shock proteins, specifically Hsp 70 and Hsp 40. Once Hsp 70 and Hsp 40 are produced, they associate with the misfolded huntingtin protein and prevent its aggregation. Earlier studies in animals affected with another polyglutamine condition, called Machado-Joseph Disease (For more on Machado-Joseph Disease, click here), have also demonstrated that the overproduction of Hsp 70 and Hsp 40 suppressed protein aggregation and subsequent nerve cell death.
In summary, recent research suggests that GA works against huntingtin aggregations by triggering the following chain of events: (1) GA binds to the heat stress protein Hsp 90, creating free HSF 1 within HD neurons; (2) the free HSF 1 triggers increased production of Hsp 70 and Hsp 40 within the cells; and (3) high levels of Hsp 70 and Hsp 40 then prevent the aggregation of mutant huntingtin.
Other studies have also revealed that GA has the potential to reduce nerve cell damage caused by HD and other polyglutamine diseases. However, GA is also known to be toxic for many cells, and this fact limits its usefulness for patient treatment over long periods of time. Still, scientists hope that drugs similar to or derived from GA can be developed into therapeutic drugs against polyglutamine diseases including HD.
Research on GA and heat shock proteins^
Sittler, et al. (2001) demonstrated that GA is capable of suppressing huntingtin aggregation in cells. To test what happens when GA is added to neurons from mice whose gene had been modified so that they express symptoms similar to Huntington’s Disease, the researchers attached a chemical marker to the huntingtin protein and watched what happened to it inside a collection of HD nerve cells. They found out that as more GA was added, the cells produced increased amounts of several heat shock proteins, including Hsp 90, Hsp 70, and Hsp 40. When a large amount of GA was added, they also found that huntingtin aggregates were reduced by as much as 80%. The researchers then wondered whether the overproduction of Hsp 90 caused the reduction of aggregates or whether it was increased production of Hsp 70 and Hsp 40 that had reduced the aggregates. They found that simply increasing the amounts of Hsp 70 and Hsp 40 without increasing the amounts of Hsp 90 is enough to reduce the aggregates. Increased production of Hsp 90 had no discernable effect on huntingtin aggregation.
For further reading:^
- Sittler, A., et al. “Geldanamycin activates a heat shock response and inhibits huntingtin aggregation in a cell culture model of Huntington’s disease.” Human Molecular Genetics. 2001 Jun 1; 10(12): 1307-15.
This article reports that Geldanamycin supplementation resulted in decreased huntingtin aggregation in HD nerve cells.
-E. Tan, 9-21-01