Cystamine
Disease Mechanism I: Protein Aggregation

A Preventer of Protein Build-up

Drug summary: Cystamine inhibits the activity of transglutaminase (TGase), an enzyme involved in the formation of of huntingtin of protein aggregates. Treating mouse models of HD with cystamine in several studies has resulted in improvements in physical symptoms and decreased nerve cell death. These results suggest that cystamine may have beneficial effects for people with HD.

Problem: Protein Aggregation

Research has indicated that the brains of people with HD become clogged with clumps of huntingtin protein called protein aggregates (also known as neuronal inclusions (NIs)). These aggregates are formed through the linking action of the enzyme TGase. By hooking proteins together into aggregates, TGase contributes to the formation of NIs.

There is still debate over the exact role of protein aggregates in the brains of people with HD. While some scientists speculate that the aggregates are involved in the disease process of HD, some studies seem to show that protein aggregates may in fact play a protective role in the HD brain. Despite the uncertainty over their exact role, however, a number of studies have shown that decreasing the number of protein aggregates could improve the condition of animal models of HD. Because of the role TGase plays in the formation of protein aggregates, scientists are looking at the effects of cystamine, a molecule that has been known to inhibit of TGase activity.

How can cystamine help treat HD?

TGase normally helps link the pieces of huntingtin protein together to form protein aggregates. In this case, the huntingtin protein is the substrate, or target, of TGase. Cystamine prevents TGase from doing its job by acting as a competitive inhibitor. Cystamine competes with huntingtin for TGase’s active site, distracting TGase from doing its normal job. Theoretically, with cystamine blocking TGase’s active site, TGase will not be able to link huntingtin proteins together and aggregates should not form.

Cystamine is also under investigation for treating HD in several other ways. It may act as an antioxidant, relieving the harmful effects caused by oxidative stress. (For more information on antioxidant treatments, click here.) Cystamine may also help prevent early cell death by inhibiting apoptosis.

Research on cystamine

Karpuj, et al. (2002) investigated how treating mouse models of HD with cystamine injections affected their physical symptoms and nerve cells. The researchers began treating the mice after seven weeks of age, when symptoms of HD had already begun to appear. Treatment was evaluated by measuring the amount of TGase activity, looking for abnormal mouse movement, charting weight loss, and counting the number of protein aggregates in the nerve cells in the brain.

Following treatment, the mice showed signs of improvement: the tremors and abnormal movement became less prominent, survival was extended by 20 percent, and weight loss was not as severe. TGase is normally very active in the mouse model of HD, but it was greatly reduced by treatment with cystamine.

To the researchers’ surprise, however, cystamine treatment did not influence the appearance or number of NIs. Instead, the researchers found increased production of the protein products of certain genes. In the fruit fly, these genes are known to exert protective effects in nerve cells against toxicity that results from polyglutamine diseases similar to HD. (For more information on polyglutamine diseases, click here.) One of the protein products of these genes, known as HDJ1 in humans and Hsp40 in mice, was found in elevated concentrations after treatment with cystamine. The researchers hypothesized that elevated HDJ1/Hsp40 in HD brains might indicate that the level of this protein was increased in a failed attempt at recovery. Releasing high levels of HDJ1/Hsp40 is probably a response to the HD disease process that was initiated by the altered huntingtin protein.

Dedeoglu, et al. (2002) examined the effects of cystamine in a mouse model of HD on TGase activity, brain and body weight, and survival. The mice received the drug in two ways: 1) through injections; and, 2) orally, in their drinking water. Treatment began when the mice were in the womb - by injecting pregnant mothers or putting cystamine in their water - and continued after birth. About 80 out of 180 mice in the first group and 26 out of 56 mice in the second group were not treated but were used for comparison to mice receiving cystamine.

The effect on survival largely depended on the dose of cystamine. In the group where mice were injected with the drug, those given the lower doses lived longer. However, all of the mice given the highest dose died, probably because of drug toxicity. The mice that were given the drug in their water survived longer than the mice that were not given cystamine at all. Injection and oral administration of cystamine were found to help survival equally at the appropriate dosage.

Both treatments also improved body weight gain compared to untreated mice. (HD often causes weight loss, so improved weight gain is sometimes thought to be a beneficial result because it combats a symptom of HD.) Also, mice treated with cystamine lost much less brain weight compared to mice not receiving cystamine treatment, which implies that cystamine protects nerve cells from degenerating in HD mice.

In the mouse model of HD, TGase activity is usually much higher than in normal mice (because, as mentioned above, TGase helps form huntingtin protein aggregates). However, when the HD mice in this study were treated with cystamine, their TGase activity fell within the normal range of non-HD mice. This finding may explain why treated mice were found to have fewer huntingtin protein aggregates. This study, along with that conducted by Karpuj, et al. (who started cystamine therapy after HD symptoms were already present), suggests that cystamine may be able to prevent protein aggregation in people with HD if given before the onset of symptoms.

Lesort, et al. (2003) recognized that cystamine probably works to treat HD in another way, in addition to inhibiting TGase. In mouse studies of cystamine, the protein aggregates were not always affected, yet other symptoms seemed to improve. This conflict led researchers to hypothesize that cystamine affects other molecules called the caspases. There are many different types of caspases, but they all contribute to early cell death in HD by playing a role in the cascade leading to apoptosis, or programmed cell death. (For more information on caspases and apoptosis, click here.)

The researchers found that cystamine inhibits a specific caspase, caspase-3, preventing apoptosis in the cells of humans with HD. Furthermore, they found that cystamine does this via a mechanism that is entirely separate from the one affecting TGase. These findings suggest that cystamine may be able to treat HD in several different ways.

While the above studies show some promise for cystamine to treat HD, it is important to note that they were conducted on mice or cells in a lab, and not on humans. More studies therefore need to be done to ensure the safety and efficacy of cystamine therapy in humans with HD.

We hope you enjoyed this section of the HOPES website. To email this article to a friend, please click here. To leave feedback for the HOPES team, click here. Make sure to specify which article you're referring to.

-K. Taub, 11/21/04

For further reading:

1. Karpuj, et al. Prolonged survival and decreased abnormal movements in transgenic model of Huntington disease, with administration of the transglutaminase inhibitor cystamine. 2002. Nature Medicine 8: 143-149. Online.
   This article reports that cystamine treatment increased survival rates and decreased abnormal movements in a mouse model of HD. It is a scientific article of medium difficulty with several technical parts.
2. Dedeoglu, et al. Therapeutic effects of cystamine in a murine model of Huntington’s disease. 2002. The Journal of Neuroscience 22(20): 8942-8950. Online.
   This article presents the research findings of a study examining cystamine in a mouse model of HD. It is a scientific article of high difficulty.


3. Lesort, et al. Cystamine inhibits caspase activity: implications for the treatment of polyglutamine disorders. 2003. Journal of Biological Chemistry 278(6): 3825-3830. Online.
   This is a highly technical article that presents the research findings of a study examining the effects of cystamine on caspases in HD cells.

Click here to return to "Disease Mechanism I: Protein Aggregation".
Click here to return to the alphabetical list of drugs and supplements.

Last Modified: 10/08/2007

An educational product of HOPES, not to be used in place of medical care. For more information about HOPES, click on the Logo. To contact HOPES with comments or questions, click here.