By tinkering with an enzyme in mouse brain cells, medical researchers may have opened the door to a treatment for Huntington's disease an as-yet- incurable progressive brain disorder. The results, which appear in tomorrow's issue of Nature show that an enzyme involved in cell suicide plays an unexpected role in the disease.
Huntington's disease is an inherited disease that causes dementia, spasms and ultimately death. Scientists know that it is caused by aberrant repetition of glutamine, an amino acid in a protein called huntingtin. Fragments of huntingtin containing glutamine sequence tuft as well as in the nuclei of brain cells and the cells die shortly thereafter. Many researchers believe that the cause of cell death is apoptosis, a programmed form of suicide. To complicate this image, called caspase enzymes are known to be involved in apoptosis in general, but also to cleave huntingtin in the test tube, where they produce fragments like those agglomerate in patients with Huntington's disease.
Harvard neurologist Robert Friedlander and his colleagues wanted to learn about the role of caspases in Huntington's disease. They studied a strain of mice with an altered gene huntingtin , which causes them to develop symptoms of Huntington-like. The team inhibited caspases in mice, either by introducing a defective copy of a gene of caspase in their genome, or by infusing a chemical inhibitor of caspase in their brains. Both strategies reported poorer physical coordination in mice and allowed to live about 20% longer than their huntingtin -altered mice that received no special treatment. And the mice that received the gene for huntingtin flawed accumulated caspase tufts fragmented slower. Because the mouse (as victims of human Huntington) had a normal copy of the huntingtin gene, they produced normal and defective huntingtin . The researchers found that fragments of the two versions accumulated in the brains of mice.
The results, says neurologist Serge Przedborski Columbia University, suggest that caspase does not just deliver the coup de grace by letting the cells of the brain cluttered with huntingtin fragments engage apoptosis; rather, the enzyme seems to be an accomplice who is on sickness. Friedlander assumes that caspase, in addition to producing aberrant huntingtin fragments, worsening matters by recruiting normal huntingtin tufts. "The results are phenomenal," says Ted Dawson neurologist at Johns Hopkins University, in particular because they show that blocking caspase may be a promising way to treat the disease.
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