What in the world do black bears have to do with treating Huntington’s disease? Believe it or not, a compound found in large quantities in the bile (a digestive fluid) of black bears may help prevent the death of brain cells in people with HD. (TUDCA) Tauroursodeoxycholic acid is also found in small quantities in human bile. It is already being used to treat a liver disease in humans.
One complication that leads to the progression of Huntington’s disease is the death of nerve cells in certain areas of the brain. There are many theories as to what causes these cells to die. At least part of the story involves the cells undergoing apoptosis, or programmed cell death. (For more information on cell death and HD click here.) Scientists are working hard to find out both what causes nerve cells to initiate apoptosis as well as how to prevent it. This chapter discusses TUDCA, a drug that may help prevent nerve cell death.
What is the theory behind TUDCA?^
A part of the cell that is especially involved in apoptosis is the mitochondrion (plural: mitochondria). Mitochondria are responsible for providing energy to the cell. If they are prevented from carrying out their jobs, the cell and its parts will not be able to perform all of their necessary functions and the cell will die. (For more information on energy and HD click here.) Mitochondria release and activate certain molecules that play a role in initiating apoptosis. When something perturbs the mitochondrial membrane, the mitochondria release a molecule called cytochrome c.
Cytochrome c then recruits enzymes called caspases to help initiate a cascade of events leading to apoptosis. Caspases are a key element in this process and are especially relevant to people with HD. The altered huntingtin protein resulting from the HD allele has more glutamines than the normal huntingtin protein. In people with HD, caspases work by cutting the altered huntingtin protein into little fragments. These fragments, in turn, activate more caspases and a vicious cycle begins. The caspases go on to participate in the cascade leading to apoptosis, while the huntingtin fragments enter the nucleus and form harmful protein aggregations called neuronal inclusions (NI). Both of these elements – many activated caspases and huntingtin fragments – contribute to a greater likelihood of early cell death in people with HD.
Much of what is known about TUDCA comes from studies done on liver cells. These studies found that TUDCA is able to prevent apoptosis and protect mitochondria from cellular elements that would otherwise interfere with energy production. One of these elements is a molecule called Bax. When Bax is transferred from the cytosol to the mitochondria, it aggravates the mitochondria s membrane, causing the membrane to release cytochrome c and initiate the apoptosis pathway. TUDCA plays an important role in preventing Bax from being transported to the mitochondria. It therefore protects the mitochondrial membrane, as well as preventing the mitochondria from activating caspases. The exact mechanism of how TUDCA works is unknown, but it has to do with protecting the mitochondria. By intervening at an early point in the apoptosis pathway and preventing the transfer of Bax to the mitochondria, TUDCA has the potential to save certain kinds of cells from early death.
How can TUDCA help treat HD?^
A group of researchers tested TUDCA in animal models of HD to see if the above theory could translate into practice. In the mouse model of HD, the effects of TUDCA were observed in three ways. First, administering TUDCA helped nerve cells in the striatum both by preventing apoptosis and decreasing degeneration. (To learn more about parts of the brain affected in HD, click here.) In both people and mice with HD, the proteins formed from the HD allele tend to clump together and clog up the nucleus by forming aggregations called neuronal inclusions (NI). Second, the mice that were treated with TUDCA had fewer and smaller NIs compared to untreated mice. Finally, at the clinical level, treated mice showed decreased motor deterioration and other HD signs as compared to untreated mice.
What is the future of TUDCA in treating HD?^
Animal studies using TUDCA to treat HD are showing some initial promise. The next step is to obtain funding and begin clinical trials to test the drug on humans with HD. Once researchers overcome this hurdle, this traditionally lengthy process may be sped up by a few key factors. First, since TUDCA is produced (albeit in very small amounts) in the human body, there should be virtually no side effects in using it as a drug. Second, it can cross the blood-brain barrier, which is usually a major obstacle to drug delivery in the central nervous system.
Delivering a drug involves getting it into the body as well as to the exact place where it will take action. Finally, TUDCA is already being used to treat a type of liver disease, so the U.S. Food and Drug Administration deems it safe for at least one particular use. Because of its neuroprotective effects, TUDCA may also be used to treat other conditions such as Alzheimer’s, Parkinson’s, and ALS. Despite all of these positive aspects of the drug, TUDCA has yet to be tested for its effects on humans with HD.
For further reading^
- Bile acid inhibits cell death in Huntington’s disease. 2002. Huntington Society of Canada. Online.
This article summarizes the research findings of TUDCA in the HD mouse model. It also provides a great low-tech explanation of apoptosis.
- Bile may treat Huntington’s. 2002. BBC News. Online.
This short article concisely summarizes the research findings of TUDCA in the HD mouse model.
- Keene, C.D. et al. Tauroursodeoxycholic acid, a bile acid, is neuroprotective in a transgenic animal model of Huntington’s disease. 2002. Proceedings of the National Academy of Sciences of the U.S.A. 99(16): 10671-10676. Online.
These are the published findings of the original study of TUDCA in the mouse model of HD. It is highly technical and only meant for a scientific audience.
-K. Taub, 11/14/2004