Searching for the Secrets of Huntington's Disease

Genetic research is beginning to hint at ways to stymie the disease by causing the defective gene for Huntington's to cease functioning or delaying the activity of proteins from the caspase family

Huntington's disease is a severe degenerative disease that usually begins to appear between ages 40 and 50. The main symptoms of this hereditary disease are loss of control over limb movement, involuntary movements, compulsive behavior, psychiatric disorders and mental deterioration. Some 15-20 years after the disease first appears, the patient will need full-time assistance. Intensive research conducted over the last five years has revealed the causes of the disease and provides an opening for developing methods to treat it and perhaps even prevent it.

Until the previous decade, it was only known that Huntington's disease is caused by the increased loss of certain brain cells in the area of the striatum, primarily responsible for controlling movement and normal behavior. When these cells are destroyed, there is a drop in the ability to perform correct movements and changes in behavior occur.

The striatum is near the area that is affected in Parkinson's disease, which is also marked by difficulties in controlling movement.

However, while Parkinson's disease entails difficulties in initiating movement and an overall drop in the number of movements made, Huntington's patients suffer from excess, involuntary movements of the limbs. These movements are dance-like, hence the disease's full name, Huntington's chorea (from the Greek word for dance). The brain damage caused by the disease affects the striatum first and foremost, but it then spreads to the other parts of the brain and leads to mental deterioration and death.

Huntington's disease is caused by a defect in a dominant gene. Each person has two copies of every gene, one copy from each of his parents. A dominant gene means that it is enough for just one of the copies of the gene to be defective in order for the disease to occur. Because every person bequeaths one copy of all the genes in his body to his offspring, children of Huntington's patients have a 50 percent risk of contracting the disease in adulthood.

The gene that causes the disease was discovered in 1993. Since then, genetic testing has been available to determine whether a fetus may contract the disease as an adult. The test also enables children of Huntington's patients to find out what their situation is, if they so desire. Despite the available genetic information, it is not possible to prevent the outbreak of the disease. The drugs that exist today can be used to treat the symptoms and improve the patient's quality of life, but they cannot prevent the disease itself.

Most of the drugs used to treat Huntington's patients are psychiatric drugs that also affect motor disturbances. According to Dr. Marietta Hanka, the coordinator of the Huntington's clinic at the Sourasky Medical Center in Tel Aviv, these drugs were originally intended for schizophrenics and sometimes cause side effects involving severe motor disorders.

One of the problems with using these drugs as well as those intended for treating motor disorders is the high price. The drugs are not included in the basket of health services."

Duplicate copies

To find a treatment that would prevent not only the symptoms, but also the disease itself, it was necessary to find out how the genetic defect causes the brain damage that appears in patients. Findings revealed that during the process of duplicating genes when the fetus is formed, Huntington's patients have an excess copy of a certain part of the gene, which usually repeats itself 10 to 20 times. The defective gene has 40 or more repetitions of this section. As a result, the protein produced by this gene is defective.

The defective gene produces a protein called Huntingtine, whose function in a normal gene is unknown. It is also not known how the defective version enters the cell nucleus, why it leads to the death of brain cells, why it specifically damages this area of the brain and why the defect, which is congenital, only causes damage at a relatively mature age.

In order to study these questions, in 1996, a genetically engineered species of mouse was created with bodies carrying the defective version of the gene that causes Huntington's disease. These mice developed motor problems, a compulsive tendency to repeat movements, tremors, and memory and learning difficulties that are also observed in human patients. The mice also developed deposits of the defective protein in their cell nuclei. Scientists discovered that the defective protein was linking up with other genes while in the nucleus and together they were changing the nature of the genes and starting a chain reaction that eventually led to the death of the cell.

During the past year, two proposals were suggested for preventing the development of the disease. In a study conducted about a year ago, mice carrying the defective version of the gene were created. This version was not active all the time. A certain drug that was given to the mice activated the defective gene or paralyzed its activity. Researchers found that activating the gene led to brain damage and the known symptoms of Huntington's disease. However, when the gene's activity was halted, the symptoms disappeared as if they had never happened and the mice resumed normal functioning. The conclusion of the study was that one day it would be possible to treat Huntington's patients using genetic methods that will cause the defective gene to cease functioning.

Another study found that it is possible to reduce the damage caused by the defective gene by delaying the activity of proteins from the caspase family. Caspases are proteins that cut other proteins in a defined place. These proteins are found naturally in the mitochondria, tiny structures that are responsible for creating accessible energy to be used by the cell. In addition to their activities in the mitochondria, proteins from the caspase family may leave for other areas of the cell and cut other proteins. One finding was that Caspase 3 is able to cut a defective Huntingtine gene. Cutting the protein into pieces enables it to penetrate into the cell nucleus.

Researchers speculate that over the years, especially in situations where the cell is damaged, there is an increased chance that the caspases will cut the defective protein. Then the protein can enter the cell nucleus and cause its death. Protein fragments piled up in the nucleus are perfect for cutting by Caspase 3. As a result of these findings, a hypothesis has emerged that a delay in the activity of these proteins outside the mitochondria may delay the development of the disease or prevent it.

Dr. Eitan Gross, of the Weizmann Institute of Science, explains that the simplest way to delay the caspases' activity is to add proteins, which also have a defined cutting area suitable for caspase activity. "That way, there will be a competition between these proteins and the proteins that the caspases usually cut, such as Huntingtine and the caspases' activity involving Huntingtine will be reduced. There are companies that are trying to develop such treatments, but it's hard to create this sort of drug without also preventing the desired activities of caspases. It's also hard to create a drug that will be specifically for this area of the brain." In addition, using a common antibiotic called Minocyclin, was also found to delay caspase activity.