Research Offers a Clue to Huntington’s


by Carl Sherman

August 3, 2009

Although the discovery of the gene for Huntington’s disease 16 years ago was a major advance, how the mutated huntingtin protein it produces wreaks neuronal havoc is still a mystery—one that has thwarted efforts to develop a drug to halt the process. [See also the Cerebrum story “We Found the Gene! Huntington’s Disease After the Cheering.”]

But researchers at Johns Hopkins University may have found the answer to one riddle within that mystery: the distribution of a small protein, Rhes, closely matches the disease’s swath of destruction. Their research was reported in the June 5 issue of Science.

“Mutant huntingtin is found uniformly throughout the body but damage only occurs in one area of the brain, the corpus striatum, and to a lesser extent the cerebral cortex,” says senior author Solomon Snyder, a professor of neuroscience at Hopkins. Why were just these areas vulnerable? “It didn’t make sense. There was something we were missing.”

Potentially toxic interaction between mutant huntingtin and other proteins “has been the focus of research in the field for some time,” says Anne Young, a professor of neurology at Harvard and founder and scientific director of the Institute for Neurodegenerative Disease at Massachusetts General Hospital. Young was not involved in the new study.

A number of proteins that bind to huntingtin have been identified, but these proteins are found all over the body, not just in the brain areas hit by Huntington’s disease. Enter Rhes—serendipitously.

“This protein is extremely obscure,” says Snyder. “We knew about it only because we’d been studying a closely related protein, dexras, for a decade” (in connection with another aspect of neurobiology, nitric oxide metabolism). From that data, the researchers saw that the few areas where Rhes was found—a high concentration in the striatum with much less in the cortex— resembled a map of the brain regions targeted by Huntington’s.

Testing alone and in tandem

Rhes was in the right place, so the Hopkins researchers decided to see if it combined with mutant huntingtin in a form capable of causing damage. They first determined that the small protein bound quite strongly to huntingtin—particularly the latter’s mutant form.

To explore the lethality of the pair, Snyder’s team did a series of experiments with cultured mouse and human stem cells they had genetically engineered to express Rhes alone, mutant huntingtin alone, or both.

“When we transfected [introduced into the cell] a gene for mutant huntingtin,” the cells were OK, Snyder says. “When we introduced a gene for Rhes, they were fine. When we put in both, they dropped dead.” The two proteins together reduced cell survival by 50 percent. This happened only with mutant huntingtin; when the researchers repeated the experiment with normal huntingtin plus Rhes, the cells were undamaged.

Like other neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, a key feature of Huntington’s is the presence of clumps of abnormal protein within many cells. But while researchers originally thought that these clumps caused disease, more recent findings in Huntington’s suggest they may serve a protective role.

For example, there are few clumps in the striatum, which is devastated by the disease, and many in the cerebellum, which is spared, Snyder says. And introducing Rhes into the cell appeared to reduce the tendency of mutant huntingtin to form aggregates, or clumps.

“Mutant huntingtin is toxic when it’s soluble,” says Srininvasa Subramaniam, who led the Johns Hopkins research team. In this dissolvable form, it can interact with the cellular machinery and enter the nucleus. When it clumps up, however, the protein appears relatively inert and harmless: Aggregation actually seems to protect the cells, he says.

 Rhes prevents aggregation by helping link a “modifier” protein to mutant huntingtin to make it soluble (a process called sumoylation). Subramaniam and his team pinpointed where in the enzymatic chain of events Rhes makes the link, then showed that by slightly altering Rhes, they could drastically cut back the sumoylation of mutant huntingtin—and blunt its toxic effects.

Second steps

“These researchers have found a novel striatal protein that can bind to huntingtin and cause toxicity, and that’s quite exciting,” Young, of Harvard, says. “It’s something that hasn’t been demonstrated by any other lab.”

But this is just the beginning, she adds: “All their research was done in cell models, and many weren’t even neuronal cells.” Further experiments should seek the same mechanism in striatal tissue slices and, ultimately, in full animal models.

Such research is underway, Snyder says. His team is mating Rhes knockout mice (animals in which the gene for Rhes has been disabled) to a strain genetically engineered to develop an equivalent of Huntington’s disease. “Presumably, knocking out Rhes should protect their progeny against the disease,” he says. “We should have some results in about a year.”

At the same time, his lab is working with others to find chemicals that might block Rhes from binding to huntingtin, in hopes that this would halt neuronal destruction.

“I think there’s considerable promise here,” says Young. “As soon as you have a small protein like this and can show it has some role in the pathophysiology of the disease, you ought to be able to use that as a target for a drug.”

The implications may go beyond Huntington’s disease, she says. “A lot of us in the field of neurodegenerative disease think that if you crack one of them, you’re likely to learn a lot more about the other disorders.” In other words, if the Rhes-huntingtin interaction proves to be a key to Huntington’s disease, it might provide leads for Alzheimer’s and Parkinson’s researchers to follow as well.