Trehalose
Disease Mechanism I: Protein Aggregation

A Protein Stabilizer

This chapter discusses a small molecule called trehalose that may help prevent protein aggregation. Everyone has a certain copy, or allele, of the Huntington gene, but people with Huntington’s disease (HD) have one copy that is longer than normal. The longer section of this HD allele consists of a repeated sequence, CAG, which codes for glutamine, an amino acid. (For more information on CAG repeats and HD, click here.) Since the Huntington gene codes for the huntingtin protein, the HD allele, with its extra CAGs, codes for a huntingtin protein with too many glutamines. The extra glutamines cause the protein to have an abnormal shape, which prevents it from functioning as it should. Instead, many of these altered huntingtin proteins clump together and trap other useful and important molecules. These “clumps” are called protein aggregates, and they may prevent the normal functioning of nerve cells. (For more information on protein aggregation, click here.) Scientists are not sure if the formation of protein aggregates is a cause or only a symptom of HD, but many agree that it would be beneficial to prevent them from forming in the first place.

What is trehalose ?

Trehalose is a disaccharide (two sugar) molecule composed of two smaller glucose molecules linked together. It is naturally produced by the body and can also be found in common foods. The U.S. Food and Drug Administration lists trehalose as a compound under the category of “generally regarded as safe.” Since trehalose is a sugar, it is used as a sweetener in products such as chewing gum. It also has a very important property that helps it to stabilize proteins and can thus be used as a biological preservative. It is this very feature that may useful for treating Huntington’s disease.

How can trehalose be used to treat HD?

A protein is made up of a string of amino acids. As the amino acids are strung together, the protein begins to fold up on itself until it gets to its final three-dimensional (3D) shape. Normal, stable proteins have no problem maintaining their shapes and functions in the cell. However, the huntingtin proteins formed from the HD allele are not very stable on their own, so they form into clumps known as protein aggregates.

Scientists think that if these proteins can be stabilized before they are fully folded, the protein aggregations will not form. One research group set out to test just that idea. They found that disaccharides are good at stabilizing molecules with extra CAG repeats, and are therefore capable of preventing protein aggregation. Trehalose was the most effective stabilizer of all the disaccharides tested. The researchers think that trehalose works by binding directly to the glutamine repeat section (the extra part of the protein that usually makes it unstable), while leaving the normal proteins unaffected.

This initial success led the researchers to test trehalose in mice that have the mouse version of HD. (Trehalose was easily administered to the mice by putting the sugar in their drinking water.) The differences between the mice treated with trehalose and the untreated mice are thus far encouraging. According to these experiments, treated mice not only live longer than untreated mice, but also fewer of their nerve cells die. In addition, the treated mice walk more easily than untreated mice and they experience later onset of the physical symptoms associated with HD.

A word of caution

The prospect of using trehalose as a treatment for HD is very exciting because it is known to be generally safe and can be taken orally. However, there are many steps between an exciting prospect and an actual, safe treatment. Even if trehalose can be easily obtained in food or as a supplement, one should first consult a physician before taking trehalose to in hopes of treating HD. While the initial results are promising, we must remember that this was only one study conducted by one group, using mice as subjects, not humans. Trehalose has not even undergone the first stage of clinical trials. Moreover, the positive effects seen in mice do not guarantee that it will work or even be completely safe in humans with HD. Since trehalose is composed of glucose, some scientists think that it might be metabolized (broken down) before it can even get to the cells in the human brain. Others think that giving a treatment made of glucose could contribute to the already elevated risk of people with HD developing diabetes.

While the current study of trehalose in HD mice is an encouraging one, only future research will demonstrate its safety and effectiveness in treating HD in humans.

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-K. Taub, 11/14/04

For further reading:

1. Alper, Joe. Delivering Huntington disease its coup de GRAS. 2004. Preclinica 2(3): 162-163. Online.
   This short article discusses the commercial and therapeutic uses of trehalose and debates the extension of it to humans. It is of medium difficulty and an important caveat to other highly enthusiastic reactions to trehalose.
2. Katsuno et al. Sweet relief for Huntington disease. 2004. Nature Medicine 10: 123-124. Online.
   This article comments on HD and other polyglutamine diseases and the recent study done by Tanaka et al. It is fairly scientific and of medium to high difficulty.
3. Pilcher, Helen R. Simple sugar eases Huntington’s disease in mice. 2004. News@nature.com. Online.
   This is an easy to understand explanation of the original study of trehalose and HD.
4. Tanaka, et al. Trehalose alleviates polyglutamine-mediated pathology in a mouse model of Huntington disease. 2004. Nature Medicine 10: 148-154. Online.
   This is the report written by the researchers who conducted the original study on trehalose and HD. It is highly technical and recommended only for a scientific audience
5. Trehalose description and manufacture. Online.
   This is a short webpage of medium difficulty that explains what trehalose is and how it is made. It has a diagram of the structural formula.

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Last Modified: 10/08/2007

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