By tinkering with an enzyme in the brain cells of mice, medical researchers may have opened the door to a treatment for Huntington's disease, an as-yet-untreatable progressive brain disorder. The findings, which appear in tomorrow's issue of Nature, show that an enzyme involved in cellular suicide plays an unexpected role in the disease.
Huntington's disease is an inherited condition that causes dementia, spasms, and eventually death. Scientists know that it is caused by an aberrant repetition of the amino acid glutamine within a protein called huntingtin. Fragments of huntingtin containing the glutamine sequence clump together in the nuclei of brain cells, and those cells die shortly thereafter. Many researchers suspect that the cause of cell death is apoptosis, a programmed form of suicide. Complicating this picture, enzymes called caspases are known to be involved in apoptosis in general but also to cleave huntingtin in the test tube, where they produce fragments like the ones that clump in Huntington's patients.
Harvard neurologist Robert Friedlander and his colleagues wanted to learn more about the role of caspases in Huntington's disease. They studied a strain of mice with a modified huntingtin gene, which causes them to develop Huntington's-like symptoms. The team inhibited caspases in the mice either by introducing a flawed copy of a caspase gene into their genome or by infusing a chemical inhibitor of caspase into their brains. Both strategies postponed deterioration of the mice's physical coordination and allowed them to live about 20% longer than huntingtin-altered mice that received no special treatment. And mice that received the flawed caspase gene accumulated fragmented huntingtin clumps more slowly. Because the mice (like human Huntington's victims) had one normal copy of the huntingtin gene, they produced both normal and faulty huntingtin. The researchers discovered that fragments of both versions accumulated in the brains of the mice.
The findings, says Columbia University neurologist Serge Przedborski, suggest that caspase does not simply deliver the coup de grâce by letting brain cells cluttered with huntingtin fragments commit apoptosis; rather, the enzyme seems to be an accomplice in bringing on the disease. Friedlander hypothesizes that caspase, besides producing fragments of aberrant huntingtin, aggravates matters by recruiting normal huntingtin to the clumps. "The findings are phenomenal," says neurologist Ted Dawson of Johns Hopkins University, particularly because they show that blocking caspase may be a promising way to treat the disease.