MEDICINE / HUNTINGTON’S DISEASE : Protein Holds Promise for Treatment
Following up on the discovery two years ago of the gene that causes Huntington’s disease, researchers have identified a key protein involved in the progression of the disorder--a discovery that opens the possibility of the first effective treatment for the hitherto mystifying disease.
Shortly after the Huntington’s gene was identified, researchers found the protein it produces, an unusually large molecule they called huntingtin that was unlike any protein previously identified.
But they did not know, and still do not, what either the healthy huntingtin protein or its aberrant form does in a cell. Huntington’s is one of the more common inherited brain disorders. About 25,000 Americans have it and another 60,000 or so carry the defective gene and will develop the disorder as they age. The slowly progressing disease, which killed folk singer Woody Guthrie, usually comes on between the ages of 30 and 50 and causes the degeneration of brain cells.
It is characterized by jerky, involuntary movements called chorea, and by dementia, a progressive deterioration of thought processes. Children of victims have a 50% chance of developing the disease.
A team from Johns Hopkins University reported Monday in San Diego at a meeting of the Society for Neuroscience that they have found a second protein, called HAP-1, that binds to the huntingtin molecule only in the brain. HAP-1 binds much more tightly to defective huntingtin than to the healthy form, and it appears that this tightly bound complex causes damage to brain cells.
“Finding [HAP-1] is like finding a gun at a murder scene,” said Dr. Christopher Ross of Johns Hopkins.
Ross and his colleagues hope to find simple drugs that can weaken this binding, thereby preventing progression of the disease.
“This is enormously exciting,” said Nancy Wexler, head of the Hereditary Diseases Foundation and a Huntington’s researcher at Columbia University. “This gives us an incredibly sophisticated, but quick and easy way to screen for new treatments.”
In other Huntington-related research reported here, scientists said they have found where huntingtin protein is localized in nerve cells, a step toward discovering its function. And a French team reported that they have developed an antibody that binds to the defective protein found in Huntington’s and four other inherited diseases, a finding that may lead to identification of the defects in a variety of still unexplained disorders.
Huntington’s may very well be the first neurodegenerative disease in which a cure is found, said neuroscientist Anne Young of Massachusetts General Hospital. “It’s going to be a model for research on other diseases,” such as Alzheimer’s and Parkinson’s.
The identification of the gene and the huntingtin protein promised to be a major breakthrough in tracing the causes of Huntington’s, but that promise has so far been delayed. The structure of huntingtin is unlike that of any other protein known, so researchers have been unable even to guess what it does in a healthy cell.
But they are beginning to eliminate possibilities. Dr. Steven Hersch of the Emory University School of Medicine reported Monday that his team had looked at the location of huntingtin in healthy cells and eliminated many possibilities. It is not located in the nucleus, it doesn’t reside in cell membranes and it doesn’t make a home in the cell’s energy-producing factories. The best guess now is that it plays a role in transporting proteins throughout the cell, he said.
Hersch and Ross also reported that huntingtin is produced in tissues throughout the body, even though its adverse effects occur only in the brain. “The targeting has been a real mystery,” Wexler said. “It’s even in toenails. Why does it only kill the brain?”
Ross’ results, which will be published next week in the journal Nature, may provide an answer to that question.
Using a yeast system recently developed at the State University of New York, Stony Brook, Ross was able to sift through rat brain tissue looking for proteins that bind to huntingtin. He found one: HAP-1. Subsequent study found that an identical protein exists in humans.
When he looked elsewhere in the body, HAP-1 did not appear. His studies show that it exists only in brain cells, and that the highest concentration is in regions of the brain that are affected most severely in Huntington’s disease.
Much to Ross’ disappointment, HAP-1, like huntingtin, is not similar to any known protein, so researchers have no clue about its normal function either. They are thus looking for other proteins that bind to HAP-1, seeking clues to its role in healthy cells. They are also screening for drugs that would reduce this bonding.
But it is the interaction between huntingtin and HAP-1 that is fascinating, Young said. And that interaction is governed by the unique nature of the genetic defect in Huntington’s.
The key feature of huntingtin is that it has, at one end, a string of many molecules of the amino acid glutamine, one of the 20 or so amino acids that are the building blocks of proteins. The number of glutamine molecules is crucial. If there are 35 glutamines or fewer, the protein is normal and does not produce disease. If there are more than 35, disease occurs.
The more copies of glutamine there are, the more severe the disease is and the earlier it develops in life. Unfortunately for affected families, the number of glutamines present seems to increase from generation to generation, so that the disease affects children at a younger age than it did their parents--a process scientists call genetic anticipation. Since the discovery of the Huntington’s gene, researchers have discovered four other rare neurodegenerative diseases in which the number of glutamines plays a role.
