Some neurons predisposed to Huntington's.

Some neurons predisposed to Huntington's

Researchers long have suspected that a buildup of certain natural chemicals or an oversensitivity to them in the brain is at least partly responsible for Huntington's disease, an inherited neurological disorder afflicting about 25,000 in the United States. According to theory, these compounds flood the bundles of neurons deep within the forebrain and kill some nerve cells, causing the progressive memory loss, angry rages and muscle spasms that mark the disease.

Now, researchers from the University of Michigan in Ann Arbor report new data concerning the exact target sites on the cells where these chemicals act. In the Aug. 19 SCIENCE they describe experiments comparing the number of receptors for six chemicals in brain tissue taken from patients who died of Huntington's and from normal brains.

The two main chemicals believed responsible for the nerve cell degeneration -- quinolinic acid and glutamate -- occur naturally and play essential roles at their normal concentrations in the body. Quinolinic acid is a breakdown product of the amino acid tryptophan; glutamate has a metabolic function as well as acting as a neurotransmitter in the brain.

But too much of either chemical kills certain cells, and past studies have shown quinolinic acid and glutamate bind to the receptor site for a chemical abbreviated NMDA. In support of this, the Michigan scientists traced glutamate binding and found that brains with Huntington's had 93 percent fewer NMDA receptors.

This indicates that cells with those receptors had died, explains principal investigator Anne Young. "Glutamate has been hypothesized to be responsible for cell death in Huntington's," she says. "But nobody had actually measured the [NMDA] receptors in post-Huntington's brains."

Not all neurons inside the basal ganglia, a knot of several kinds of nerve cells in the forebrain, degenerate in Huntington's victims. Some cells almost completely die off, while others are unscathed. Several years ago, scientists from the University of Maryland in Baltimore injected quinolinic acid into normal rat basal ganglia and found the same patterns of cell death and survival as in Huntington's patients (SN: 1/29/83, p.70). Quinolinic acid works at the same receptor site as glutamate, Young says.

In two studies comparing a total of 13 Huntington's brains to 12 controls, Young and her colleagues found decreased numbers of receptors for five other chemicals, although none as pronounced as the decrease in NMDA receptors. Receptors for two other compounds were diminished by 67 percent and those for three others by 55 percent or less. Young plans to do the same type of comparison on patients who died before the disease progressed as far as in the Huntington's brains in the current study.

In the end, the Michigan researchers suggest that some cells may be more vulnerable to damage from glutamate and quinolinic acid because they contain more NMDA receptors where the compounds can bind to the cell. Finding a way to block those receptors, they say, might slow the disease, for which there is still no cure.