Like any city of the '90s, a well-run cell needs a good recycling program. That program seems to go awry in a rare degenerative disease of the nervous system called spinocerebellar ataxia type 1 (SCA1), caused by a mutation similar to the one behind Huntington's disease. Now researchers report in this month's Nature Genetics that they have succeeded in improving the recycling of unruly proteins in mouse cells bearing the SCA1 mutation. But experts say it's uncertain whether this test tube success will lead to better therapies for the disease.
The DNA of people with SCA1 contains sequences that repeat like a scratched record. The DNA provides instructions for assembling proteins for normal cell function. But when the cell gets to the "broken record" part of the instructions, it makes a protein with far too many copies of a molecule called glutamine. "We hypothesize that having such a long glutamine repeat causes the protein to fold improperly," says Huda Zoghbi, a molecular geneticist at the Baylor College of Medicine in Houston. From previous work, Zoghbi also knew that proteins with long glutamine tracts collect into clumps, or "aggregates," inside the nucleus of brain cells of mice altered to get the disease just before the animals develop symptoms.
After experiments suggested that mouse and human brain cells were failing to dispose of the aggregates, the researchers tried the equivalent of hiring more custodians. They inserted a new gene into cells that carry the mutant protein. In test tubes, this gene caused the cells to produce extra amounts of a chaperone molecule that ordinarily helps a cell recognize misfolded proteins. Although the researchers don't know precisely how the chaperone molecule works, the difference was unmistakable: Less than 40% of cells treated with gene therapy had clumps, compared to 70% of controls.
Though SCA1 is very rare, experts believe that its protein abnormalities resemble those in more common neurological diseases, such as Huntington's or Alzheimer's. "There's increasing evidence that the same biological phenomenon is occurring in all these diseases," says Henry Paulson, a neurogeneticist at the University of Iowa.
But it's unclear whether chaperones can help. For one thing, researchers don't know yet whether faulty cellular waste removal is the cause or merely a symptom of such diseases. "The bottom line question," says Christopher Austin, a neurogeneticist at Merck Research Laboratories in West Point, Pennsylvania, is whether this kind of gene therapy can stem the rate of brain cell death. "That question has not been addressed," he says.