STANFORD, Calif. - Stanford University Medical Center researchers have discovered a potential treatment for Huntington's disease. By enhancing the brain's natural protective response to the disease, researchers were able to alleviate the uncontrollable tremors and prolong the lives of mice with a neurological disorder that mimics Huntington's. Their finding suggests that a similar treatment strategy may be effective in humans.

"This is exciting because it has implications for therapy," said Lawrence Steinman, MD, professor of neurological sciences and pediatrics and senior author of the study, published in the February issue of Nature Medicine.

Huntington's disease is a hereditary disorder characterized by memory loss, abnormal movement and premature death. It affects 1 in 10,000 people, and children with an affected parent have a 50 percent chance of developing the disease.

An abnormal form of the gene called huntingtin is at the root of the problem. In healthy individuals, the huntingtin gene encodes a protein with 6 to 34 glutamine molecules - one of the essential building blocks of proteins - at one end. When the number of glutamine molecules at the end of the protein exceeds 36, Huntington's disease results. But the normal gene function remains a mystery.

According to earlier research, the brains of Huntington's patients become clogged with clumps of protein called aggregates. The aggregates are made up of the abnormal huntingtin proteins hooked together. The aggregations are formed by the action of an enzyme called transglutaminase and by the tendency of these proteins to stick together.

If the aggregates are the cause of the disease, Steinman reasoned, perhaps the disease could be controlled by preventing the two proteins from clumping into aggregates. He already knew that a compound called cystamine could keep the sticky protein, transglutaminase, under wraps.

So, his former graduate student, Marcela Karpuj, PhD, now a postdoctoral fellow at University of California San Francisco, began treating their sick mice with cystamine injections. The treated mice showed signs of improvement; the tremors and abnormal movements became less severe, and the lifespan of the mice increased by 20 percent on average.

But to the researcher's surprise, the protein aggregates remained unchanged.

"The story, because it is science, took an unexpected turn," Steinman said. "We expected cystamine to inhibit the aggregations."

Paper co-author Mark Becher, chief of neuropathology at the University of New Mexico Health Sciences Center, examined the brains of these mice, and found aggregations were the same after treatment, Steinman said.

This result set the Stanford team off on a "hypothesis-finding expedition." They began to screen the brains of cystamine-treated and untreated mice, looking for any differences in gene expression between the two groups.

The researchers found that mice treated with cystamine had elevated expression of three particularly interesting genes - all of which are known to encode proteins that play a protective role in the brain. These same neuroprotective proteins were found at increased levels in the brains of human Huntington's patients. This finding suggested that the brain makes an unsuccessful attempt to protect itself against the disease.

"It seems the brain under attack has a number of defense mechanisms turned on to sop up toxic brain proteins, lead them away to digestive compartments, and out of the neuron," Steinman said. "This allows the neuron to survive, which is important since mammalian brains are bad at regenerating neurons."

Though these findings suggest that cystamine could someday offer hope to patients with Huntington's disease, the quest for other potentially better compounds will continue.

"Before trying this with humans, we will search for ever more effective and specific compounds," Steinman said. "On the other hand, this is a horrendous, fatal disease. So we will have to see at what pace it will be applied to humans."

In recent years, other compounds have also been reported to extend the lives of mice suffering from Huntington's, Steinman said. Perhaps multiple treatments in combination would have even greater benefits, he added.

Marcela Karpuj, primary author of the study, is optimistic about the results. "I think this is very exciting," she said. "In the future, treatments to raise the levels of neuroprotective proteins could be given to humans and could be therapeutic for other neurodegenerative diseases as well."

Funding for the study was provided by the Hereditary Disease Foundation and the National Institutes of Health.

---Stanford University

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