Researchers Identify Possible Key to Huntington’s Disease

Huntington’s disease (HD) is a progressive, degenerative disease that causes nerve cells, or neurons, in certain areas of the brain to waste away, resulting in uncontrolled movements, emotional disturbances, mental deterioration and death. In the United States, HD became familiar to many people in the 1950s when popular folk singer Woody Guthrie became ill with the disease. Until recently, however, scientists understood very little about HD. It wasn’t until 1993 that scientists were able to identify the gene that causes the complex disorder, and not until August 2008 was there a drug approved for use in the U.S. to treat its symptoms, though there is no way to stop or reverse the course of HD. But, as Woody said in one of his songs, “it don’t take much to realize that all this stuff takes time,” and now a long-awaited discovery may change all that.

Scientists have known that the gene which causes HD, passed down from parent to child, produces a mutant version of a protein, called huntingtin or mHtt, that gathers in all cells of the body. But what they didn’t understand was why only the cells in a particular part of the brain, the striatum, deteriorated. So researchers at Johns Hopkins University began to search for proteins that interacted specifically with the mHtt protein in that part of the brain. They uncovered a little-known protein named rhes, which is found almost exclusively in the striatum area of the brain.

Using human embryonic cells and brain cells taken from mice, the researchers found that when both mHtt and rhes were present in the cells, half the cells died within 48 hours, but rhes or mHtt alone did not cause cell death. “Up until now, nobody had the vaguest notion of what was the cause of the brain damage and the death,” said Dr. Solomon Snyder, professor of neuroscience at Johns Hopkins and whose team reported the findings in the journal Science. “Here’s the rhes protein, we’ve known about it for years. Nobody ever really knew what it did in the brain or anywhere else, and it turns out it looks like the key to Huntington’s disease.”

The researchers also did a set of experiments to learn more about the role of rhes. Previous research has shown that the abnormal mHtt proteins form clumps in cells throughout the body and brain, but fewer in the striatum. When the researchers added rhes to cells with abnormal mHtt, it led to fewer clumps, but the cells died, which suggests that the action of unclumping the proteins caused the cell death. The team is currently testing to see if removing rhes from mice with HD can slow or stop brain cells from dying. “Now that we’ve uncovered the role of rhes, it’s possible that drugs can be designed that specifically target rhes to treat or even prevent the disease,” Snyder said.

This breakthrough may also offer insight into other brain-destroying diseases like Alzheimer’s, which are also distinguished by clumps, also called aggregates, of some type of faulty protein. “The answers in one disease may have implications for another,” said Dr. Walter Koroshetz of NIH’s National Institute of Neurological Disorders and Stroke. “There’s been people on both sides of the fence. This story plays to the role of the aggregates as not being the major problem but the soluble protein as being the major problem.”
 
Experts estimate that one in every 10,000 persons—nearly 30,000 in the United States—have HD. At least 150,000 others have a 50 percent risk of developing the disease and thousands more of their relatives live with the possibility that they, too, might develop HD.