Scientists have solved a mystery surrounding a horrific illness: Why people with Huntington's disease harbor a faulty protein throughout their bodies but it destroys only certain brain cells.
The discovery may provide a long-awaited target for developing treatments for the incurable killer — and also may have ramifications for more common brain diseases like Alzheimer's.
"Up until now, nobody had the vaguest notion of what was the cause of the brain damage and the death," said Dr. Solomon Snyder of Johns Hopkins University, whose team reported the findings in Friday's edition of the journal Science.
"This is a significant step forward," said Dr. Walter Koroshetz, deputy director of the National Institutes of Health's brain division.
Huntington's is a rare inherited disease — there are an estimated 30,000 U.S. patients — that typically strikes in the late 30s or early 40s. What starts as uncontrollable twitches and jerks and deterioration of mental abilities inexorably worsens until patients can barely eat, speak or walk. Death occurs a decade or more after symptoms begin.
One mutated gene is the cause. A child of a Huntington's patient has a 50-50 chance of inheriting that gene, and anyone who does will develop symptoms at some point if they live long enough. Scientists discovered the gene in 1993, giving families the hard choice of whether to be tested to learn who escaped that fate and who didn't.
But 16 years later, there is only one treatment to ease the writhing movements and little progress toward the bigger goal — finding some way of slowing or stopping the disease from carving a hole in patients' brains.
Enter the new research. The bad Huntington's gene creates a faulty protein that is found in all cells. Yet the only cells that die are certain neurons, mostly those in a movement-controlling brain region called the corpus striatum that by the time patients die is so ravaged that it's tissue-paper thin.
Why? A second protein is the culprit, Snyder's team discovered. It's a little-known molecule named Rhes that is found almost exclusively in the striatum. When Rhes mixes with the mutated Huntington's protein it sparks a chemical reaction, the researchers reported.
First came a simple experiment: They used human embryonic cells and brain cells taken from mice. To each, they mixed in different combinations of the mutated Huntington's protein, its normal version, and Rhes. Only when both the mutant protein and Rhes were in the same cells did those cells start dying.
Then the researchers teased out just what made the chemical reaction, named sumoylation, so toxic. It seems that cells may try to deal with the mutated protein by clumping it out of the way, almost like creating a garbage heap. Adding Rhes led to less clumping along with cell death, suggesting that it's the soluble form of the faulty protein that's dangerous.
And that's the connection to other brain-destroying diseases like Alzheimer's. Most are distinguished by clumps of some type of faulty protein, and there's a raging debate among scientists about whether the clumps, also called "aggregates," are the cause of brain destruction or a frantic attempt by the brain to save itself.
"The answers in one disease may have implications for another," noted 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."
Dr. Nancy Wexler of the Hereditary Disease Foundation, who helped lead the Huntington's gene discovery, called the work a "fabulous experiment" and praised the Hopkins team for quickly publishing the Rhes reaction so that other researchers could start hunting ways to block it.
"This is a very promising avenue," she said.
One next step is to see whether removing Rhes from mice with Huntington's disease slows or prevents the brain cell death without causing too many side effects. If so, the quest would be for a drug to block that protein.