November 13, 1995
Media Contact: Michael Purdy
Phone: (410) 955-8725
Johns Hopkins scientists have identified a potential direct protein link in the chain reaction that causes Huntington's disease, a link that may provide a target for novel drugs to treat the fatal disease.
Huntington's Associated Protein-1 or HAP-1, became known by the company it keeps: it's the first protein ever found that chemically binds to huntingtin, the protein produced by the Huntington's disease gene itself.
"The identification of HAP-1 represents the first discovery of a protein which can directly associate with the protein made by the Huntington's disease gene," says Chris Ross, M.D., Ph.D., an associate professor of psychiatry and neuroscience. "Finding it is like finding a gun at a murder scene."
Further evidence suggests that HAP-1 may be the "smoking gun" of Huntington's: so far, it has only been found in the brain, where Huntington's disease causes its damage. Also, HAP-1 binds more tightly to huntingtin as the severity of the Huntington's gene mutation increases.
(The Huntington's mutation is an abnormally long sequence of genetic code known as a triplet repeat; the longer the sequence, the earlier a patient develops Huntington's and the more tightly HAP-1 binds to huntingtin.)
Huntington's disease is an inherited neurodegenerative disorder that currently afflicts 25,000 persons in the United States. Approximately 150,000 people have the mutant gene that leads to the disease. Symptoms, which typically only begin to appear in middle age, include difficulty in coordinating movements, involuntary movements called chorea, impairment of thinking, depression, and manic-depression. There is no known treatment, and patients who develop the disease die within 15 to 20 years.
Although the Huntington's Disease Collaborative Research Group cloned the gene for the disease in 1993, it bore no resemblance to previously known genes and knowledge of its sequence did little by itself to uncover the disease process.
"We know that huntingtin, the protein produced by this gene, is necessary for development and appears to be active throughout the body," says Ross. "But Huntington's disease selectively kills neurons in the brain, not cells everywhere in the body, suggesting that in Huntington's disease there is an abnormal interaction that takes place between huntingtin and a brain protein."
Ross and colleagues at Hopkins searched for possible interactions with a technology known as the yeast-two hybrid system, which revealed biochemical bonds between parts of the huntingtin protein and portions of HAP-1 from rat brains. They confirmed the interaction by inserting copies of the rat HAP-1 gene into bacteria and getting the gene to make its corresponding protein on cue.
The researchers later found a portion of the HAP-1 gene in humans, and similar tests showed that the human form also binds to huntingtin. So far, they have only been able to find HAP-1 production in the brain.
"We already know a great deal about the damage Huntington's creates in nerve cells; now that we suspect HAP-1, we can test its potential for creating that damage," says Ross.
For example, Ross says, Huntington's triggers self-destruct processes in brain cells. Researchers can test for any interaction between HAP-1 and the proteins involved in these self-destruct processes.
They also could try to breed a mouse in which the gene for HAP-1 has been knocked out. If that mouse survives and produces offspring, the new line of mice could be crossbred with mouse models of Huntington's disease to see if the crossbreeds are vulnerable to the disease.
Researchers can use the same technology that found the interaction between huntingtin and HAP-1 to look for drugs that dampen this bond.
"Presumably, we would only have to decrease the interaction back to the strength present in unaffected individuals to get a beneficial effect for Huntington's patients," says Ross.
"Finally, insights from HAP-1 may have applications in other disorders. Right now, we know of four other neurodegenerative diseases that result from a similar type of genetic mutation, and there are theories that some psychiatric disorders may result from mutations of this type," Ross says.
Ross will publish his findings on HAP-1 in the Nov. 23 issue of Nature. Lead authors on the HAP-1 study are Xiao-Jiang Li and Shi-Hua Li; other authors were Alan Sharp; Frederick Nucifora Jr.; Gabriele Schilling; Anthony Lanahan; Paul Worley; and Solomon Snyder, M.D., director of Hopkins' Department of Neuroscience.
The research was supported by a grant from the National Institute of Neurological Disorders and Stroke, as well as a bequest to the Huntington's disease program at Johns Hopkins from the estate of Nora May Gee.
A patent on the HAP-1 cDNA sequence and its use for screening for drugs to treat Huntington's is being filed by Hopkins.