Collaring Suspect Protease Slows Huntington's in Mice
Although the gene for Huntington's disease was one of the first disease genes identified, there still is no effective treatment. One possible route to slowing the disease is reported in the May 20 Nature by a team of researchers at Brigham and Women's Hospital, Massachusetts General Hospital, and HMS. In their article, lead author Victor Ona, a postdoctoral fellow in the lab of Robert Friedlander, assistant professor of surgery at BWH, and colleagues show that inhibition of caspase-1, a protease, slows progression of the disease in a mouse model of Huntington's.
    The molecular cause of neuronal degeneration in the disease is not clear, but the huntingtin gene, linked to the disease in humans, contains long tracts of the amino acid glutamine. Mice expressing part of the gene containing these tracts mimic the symptoms of afflicted humans, including the uncontrollable limb movements and irregular gait.
    To test the role of caspase-1, the researchers inhibited caspase activity with continuous drug perfusion to the animal's brain and generated Huntington-afflicted mice containing a dominant negative form of caspase-1, which inhibits normal caspase function. They then looked at molecular markers characteristic of the disease, longevity of the animals, age of onset of the disease, and physical dexterity. In all tests, animals with lowered caspase-1 levels showed significantly less severe symptoms or a later age of onset.
    Interestingly, though caspase-1 is involved in apoptosis, disease progression is more dependent on cell dysfunction than cell death.