Stanford University Medical Center researchers have discovered what they believe may be a potential treatment for Huntington 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 that were artificially carrying the gene that causes HD. 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 2002 issue of Nature Medicine.

In their research, investigators injected the compound “cystamine” into HD mice. They were expecting to see the compound have a direct effect on the process of the development of toxic protein aggregates in the brain. These aggregates are known to speed up brain cell death, and play a critical role in the progression of the disease. However, while they were expecting one result, they actually got a different, unexpected reaction.

Cystamine had no impact on the process of protein aggregation. Instead, the researchers found that mice treated with cystamine had higher levels of three particularly interesting genes, all of which are known to produce proteins that play a protective role in the brain. These same proteins – known as “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 Huntington 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.”

Can you translate that for me?

Based on this study, researchers believe that Huntington disease causes certain proteins to be produced in affected brain cells to try and protect them against the effects of HD. These proteins, known as “neuroprotective proteins” act like bouncers at a bar. First, they attach themselves to the toxic protein huntingtin. Then they drag the toxic huntingtin out of the nucleus of the cell (the brain cell’s control centre), and take it into the body of the cell. From there they drag the huntingtin to a place in the cell where enzymes “eat” the toxic huntingtin, and destroy it. However, enough huntingtin builds up that even the neuroprotective proteins can’t completely stop, only slow down, the process leading to the death of the brain cells.

By using cystamine, Dr. Steinman and his team “boosted” the brain’s natural defences, and this is what caused the positive effect in the mice.

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

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.” – SM/Office of News and Public Affairs, Stanford University, California