The group performed a genetic experiment known as a loss-of-function suppressor screen, which searches for genes that, when switched off, reduce the toxic effects of the mutant protein associated with Huntington's. One of the genes they identified encodes an enzyme, called KMO, that has been previously implicated in the disease. The enzyme functions in a metabolic pathway that is activated at early stages of the disease in people with Huntington's, as well as in animal models of the disease.

"The nice thing about this finding is that there is a chemical compound available that inhibits KMO activity," said Dr. Paul Muchowski, assistant professor of pharmacology at the UW, who led the study. "We're in the midst of testing that compound in a mouse model of Huntington's disease."

Further support for KMO as a therapeutic target for Huntington's disease comes from a recent study led by Dr. Aleksey G. Kazantsev of Harvard Medical School. In this study, researchers used cell-based experiments to screen about 20,000 chemical compounds, and identified one that suppresses neurodegeneration in a fly model of the disease. That compound has a very similar chemical structure as the drug that inhibits the target identified by Muchowski's group. The results appeared in the Jan. 18, 2005, issue of the Proceedings of the National Academy of Sciences.

In addition to finding a potential drug target for future Huntington's treatment, the study by Muchowski and his colleagues could take research on the disease in a new direction: towards microglial cells, which are immune cells in the brain. Previous research has focused exclusively on neuronal cells, but the enzyme KMO is found predominantly in microglial cells. Since inhibiting KMO activity has a direct effect on toxicity of the mutant protein associated with Huntington's, that could mean microgial cells are home to an important step in progression of the disease.

Huntington's affects an estimated 30,000 people in the United States. It is characterized by loss of motor control and cognitive functions, as well as by depression or other psychiatric problems.

uwmedicine/