Almost 20 years ago, a team of scientists removed brain cells from people with the neurodegenerative disorder Huntington's disease and scrutinized them under a powerful electron microscope. Deep inside the cells, in the DNA-carrying sac called the nucleus, the investigators found mysterious clumps.
The report was "buried in the literature. Nobody paid any attention to it at all," says Gillian P. Bates of Guy's Hospital in London.
Somebody should have. Resurrecting that long-forgotten observation, Bates and her colleagues have studied mice genetically engineered to develop Huntington's disease and now report that the mutant proteins they produce aggregate in the nuclei of some brain cells. These protein clumps may harm the nucleus and lead to the cell's eventual death.
"We and at least one other laboratory do see these same lesions in Huntington's disease patients," adds Christopher A. Ross of Johns Hopkins Medical Institutions in Baltimore, citing preliminary observations in brain tissue removed during autopsies.
Other researchers have detected similar deposits in the brain cells of people with spinocerebellar ataxia type 3 (SCA3), another neurodegenerative disease.
These findings suggest that a common mechanism exists for the cell death seen in a whole family of brain diseases.
"We're now tying a these diseases together in that there's an alteration in the nucleus taking place because of mutant proteins. There's a unifying theme, at least to one step in the diseases," says Huda Y. Zoghbi of Baylor College of Medicine in Houston. She and Harry T. Orn of the University of Minnesota in Minneapolis have seen nuclear protein deposits in mice with a condition similar to the human disease spinocerebellar ataxia type 1.
The new research has offered hope to investigators seeking to thwart the inexorable decline of people with Huntington's disease and similar brain disorders. They speculate that physicians could cure or delay the diseases with compounds that reduce the buildup of the mutant proteins. "You might not need to slow it down much to have a dramatic effect," says David E. Housman of the Massachusetts Institute of Technology.
Huntington's disease and the other illnesses under investigation result from unusual mutations that some scientists call a genetic stutter (SN: 6/10/95, p. 360). In each disorder, a gene contains abnormally long stretches of DNA known as CAG repeats. The extra CAG repeats add copies of an amino acid, glutamine, to the protein normally encoded by the gene. …