Huntington's disease: clues to the culprit.

Huntington's disease: Clues to the culprit

Huntington's disease starts with a genetic defect on the short arm of chromosome 4, and leads to a withering of the brain. The result: the victim's involuntary participation in a grotesque "chorea" -- a jerky dance of the muscles -- and dementia. Beginning and end are known, but the agent of the disease inside the body has been a mystery.

Now, researchers at Stanford University report evidence that the culprit in Huntington's disease may be one of a group of compounds called excitotoxins. According to Dennis Choi, who led the study, the work further suggests that research should focus on one of the three types of neuronal receptors for excitotoxins. He speculates that the degeneration of nerve cells in the brain seen in the disorder is triggered by the improper activation of this receptor, called the NMDA receptor. If borne out, the work may someday provide a basis for therapeutic intervention in Huntington's.

The work, reported in the Oct. 3 SCIENCE, is the latest jump in a game of research leapfrog between Choi's group and one led by Joseph Martin of Harvard Medical School. A year ago, Martin showed that the destruction of nerve cells in Huntington's does not proceed wholesale in certain areas of the brain, as had been thought, but instead shows a distinctive pattern: One group of neurons, containing the enzyme NADPH-d, is to some extent spared. The finding "showed that the natural disease process doesn't just blow away [all] the neurons," Choi says. "It leaves a fingerprint, and any hypothesis must account for it."

In the search for an offender to match the fingerprint, both groups have looked at the excitotoxins. These compounds have paradoxical actions: They can excite a neuron to fire or they can kill it, probably depending on length of exposure, according to Choi. But though they are potentially dangerous, some excitotoxins are present in "stupendous amounts" in the brain, Choi says. That has made them a suspect in many neurological disorders. With a simple failure of the mechanisms that normally compartmentalize or clean up excitotoxins, there is the potential for widespread neuronal destruction. "It's as though you were running around with a can of gasoline in one hand and a match in the other," Choi says.

Martin's group recently reported that they were able to produce the Huntington's pattern of neuronal destruction by injecting the excitotoxin quinolinic acid into rat brains. (A group at the University of Maryland in Baltimore had first suggested that quinolinic acid might be the agent.) The Harvard group speculated in the May 8 NATURE that the NADPH-d neurons survive in Huntington's because the enzyme enables them to degrade quinolinic acid.

Now, Choi's group reports that in vitro the NADPH-d neurons appear to be resistant to the entire class of excitotoxins that act selectively at the NMDA receptor. At the same time, these neurons are unusually vulnerable to excitotoxins that act at either of the other types of receptors. The researchers suggest that the neurons are spared in Huntington's because they have fewer NMDA receptors -- and therefore are less exposed to the excitotoxins specific to that class of receptor -- not because the neurons are better equipped against quinolinic acid.

That would have research and clinical implications. In the search for the culprit in Huntington's, it points toward the compounds that act specifically on the NMDA receptor. And, while a cure for Huntington's will probably wait on the ability to intervene on the genetic level, selectively blocking NMDA receptors "might delay the onset of Huntington's from 45 years of age to 55 or 65," Choi says. "That's still a huge therapeutic benefit."

Martin now plans to survey the distribution of excitotoxin receptors in the brain, to see if the NMDA receptro-Huntington's link holds up.