Protein Activator Revealed Responsible for Brain Cell Damage in Huntington's Disease

Neuroscientists have discovered why a defective protein accumulates in cells everywhere in the bodies of individuals with Huntington's disease (HD), but only kills cells in the area of the brain that controls movement, causing insignificant damage to tissues elsewhere. The answer lies in one tiny protein called Rhes that is found only in the part of the brain that controls movement. The findings help explain the distinctive pattern of brain damage in HD and its symptoms, as well as offer a new approach for new therapy.

HD itself is caused by a genetic defect that produces a mutant version of the protein huntingtin, which collects in all cells of the body, but only appears to affect the brain. Passed from parent to child through an alteration of a normal gene, HD over time causes irreversible uncontrolled movement, loss of intellectual function, emotional disturbances, and death.

"It's always been a mystery why, if the protein made by the HD gene is seen in all cells of the body, only the brain, and only a particular part of the brain, the corpus striatum, deteriorates,” said Solomon H. Snyder, M.D., a professor of neuroscience at Johns Hopkins University (Baltimore, MD, USA). "By finding the basic culprit, the potential is there to develop drugs that target it and either prevent symptoms or slow them down.”

Curious about the huntingtin protein's striatal-specific effect, Dr. Snyder's research team, led by Srinivasa Subramaniam, Ph.D., a postdoctoral fellow, looked for proteins that interacted locally, specifically, and only with huntingtin in the corpus striatum, guessing that the molecular answer to the mystery most likely would be found there.

The protein Rhes caught the investigators attention because they already were studying a related protein for other reasons. Rhes was known to be found almost exclusively in the corpus striatum. Conducting tests using human and mouse cells, they found that Rhes interacted with both healthy and mutant versions of huntingtin protein, but bound much more strongly to mutant huntingtin (mHtt). "Touching or binding is one matter, but death is altogether another,” said Dr. Snyder, so the next step was to see whether and how Rhes plus mHtt could kill brain cells in the corpus striatum.

Utilizing human embryonic cells and brain cells gathered from mice the researchers added different combinations of normal and mutant huntingtin and Rhes, and examined the cells over the next week to see if any cells died. While each protein alone did not alter the number of cells in the dishes, when both mHtt and Rhes were present in the same cells, half the cells died within 48 hours. "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,” said Dr. Snyder. "And it turns out, it looks like the key to Huntington's disease.”

The researchers then went on to confront another mystery surrounding the disease, the solution to this one adding further evidence for the role Rhes plays in HD. "We've known for a long time that abnormal huntingtin proteins aggregate and form clumps in all cells of the body, but the corpus striatum of HD patients seems to have fewer of these clumps than other brain regions or the rest of the body,” said Dr. Subramaniam in describing the mystery. "This has led to much controversy: are the clumps toxic, or is it the lack of clumps that's toxic to these brain cells?”

In the study, adding Rhes to cells with abnormal huntingtin led to fewer clumps, but the cells died. The results, according to Dr. Subramaniam, suggest that Rhes might be responsible for unclumping mutant huntingtin protein and this somehow kills cells. "Since Rhes is highly found in the corpus striatum, clumping somehow protects cells in other tissues of the body from dying,” he noted.

The researchers are now exploring whether removing Rhes from mice with Huntington's disease can suppress 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,” stated Dr. Snyder.

The study was funded by a U.S. Public Health Service grant and Research Scientist Awards, and the findings were published in the June 5, 2009, issue of Science.

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