HD research news - medical research into treatment & prevention

Important new research findings

By Will Dunham

March 2001

WASHINGTON (Reuters) - In a finding that could lead to a cure for Huntington's disease, scientists on Thursday said they have determined how the gene responsible for the fatal hereditary disease kills nerve cells in a key part of the brain.

Researchers at Johns Hopkins University in Baltimore found that in brain cells marked for destruction by the progressive brain-wasting disorder, a mutant protein "hijacks" a key molecule in a cell's survival system. In laboratory cultures of human cells containing the mutant Huntington's disease gene, researchers were able to reverse impending cell death.

Dr. Christopher Ross, who led the study, said the findings could lead to the development of an effective drug treatment for Huntington's disease (HD), which affects about one in 10,000 people, including 25,000 to 30,000 Americans.

"We use the word (cure) a lot. We use it carefully," Ross said in a telephone interview.

"What we're really aiming for is something more like in diabetes where we know this will be (merely) a chronic disease," he added. "At least for diabetes, once you find the mechanism - loss of insulin - and can treat it, you can convert it into something people can live with for a long period of time. That's kind of what we're aiming for with HD. And that would be, in some sense, a cure."

The findings appeared in the journal Science.

Huntington's disease, first described in 1872 by American Dr. George Huntington, is a fatal hereditary disorder marked by the wasting of nerve cells chiefly in the part of the brain that helps control movement and thought.

Symptoms typically begin in adulthood - between the ages of 35 and 50 -usually as uncontrollable movement. That is followed by progressive loss of mental function, including personality changes, loss of speech, abnormal facial and body movements, and eventually death. The disorder is inherited as a single faulty gene on human chromosome No. 4. The gene was discovered in 1993.

How did the Disease Kill the Brain Cells?

Researchers said their goal was to understand the mechanism used by the Huntington's gene to kill a small patch of vital nerve cells in the brain in order to concoct a way to interfere with the process early on with drugs. Ross said scientists have known that the abnormal gene produces a flawed form of a protein called huntingtin, which has too many repeats of glutamine, one of its amino acid sub-units. Thus, brain cells of HD patients show clumping of the flawed huntingtin.

The clumped molecule by itself apparently is not harmful. But scientists said it attracts and becomes entangled with a smaller, critical protein in the cell nucleus called CBP. This so-called regulatory molecule gets pulled away from its place alongside DNA and becomes entangled and useless, meaning a pathway crucial for cell survival never gets activated.

To demonstrate that CBP gets hijacked, the researchers attached different colored fluorescent markers to DNA, huntingtin and CBP and watched what happened inside cells to which they had added mutant HD genes. They also showed the process in live mice carrying the human HD gene and in brains of dead human HD patients.

The researchers said they were able to reverse the process in a test tube, turning around the cells' slide into death. They said they had not yet demonstrated the turnaround in a live mouse. But they said the findings offer a target for developing and testing new drugs to treat Huntington's.

"It's A Very Exciting Finding"

"This has been a tough problem," Ross said. "The gene was discovered in 1993. Pretty soon after, we understood that the gene makes an abnormal protein and it's the protein that causes the disease. And we've really been searching for how the protein causes the cell death."

"People have looked at lots of other proteins. And this is the first one where we think we have really strong evidence that this is actually the mechanism of cell death. And assuming we're right, it's a very exciting finding because it's so easy to develop a drug screening assay (testing scheme) from it."

About eight other rare neurodegenerative diseases are caused by the same mechanism, Ross said, meaning that treatments for them also could be one step closer. They include the spinocerebellar ataxias, a set of rare debilitating diseases of movement and gait.

The study was funded by the nonprofit Huntington's Disease Society of American (HDSA), the Hereditary Disease Foundation and the U.S. National Institute for Neurological Disorders and Stroke. NDSA Executive Director Barbara Boyle said she hoped such research would "make this the last generation with HD."