In 1979, researchers from the Columbia University College of Physicians and Surgeons in New York viewed HD changes in biopsied human brain cells and described the damage as clumps, fibers, and masses in the cell nucleus. The Bates and Davies group and a second international team of investigators have now, nearly 20 years later, explained what the Columbia researchers found. Using new "transgenic" mice developed by Dr. Bates to contain a disease-causing fragment of the human HD gene, the researchers saw in the nucleus of each mouse brain cell a rough, grainy, circular, sometimes fiber-fringed structure that strikingly resembled structures seen by the Columbia University researchers in the brain cell nuclei of people with HD. The Bates group labeled them neuronal intranuclear inclusions (NII). Analysis using monoclonal antibody technology not available in 1979 revealed that NIIs were aggregates (clumps) of huntingtin protein. The protein entered the cell nucleus through pores in the nuclear membrane. The NII were present in the brain cell nuclei of mice with symptoms very similar to HD and absent in non-transgenic control mice.
"This radically changes our framework for thinking therapeutically," says Dr. Wexler, who is also the president of the Hereditary Disease Foundation in Santa Monica. "Is there a way to prevent the protein from clumping, to break up clumps once they've formed, to keep it out of the nucleus or to attack the mysterious signals that start the process?
"In early development, when everything is normal, the protein is swimming in the cytoplasm like Odysseus sailing in his boat," she explains. "He hears the siren song of Circe and ends up marooned in the nucleus instead of going home."
Dr. Wexler is "ecstatic" about these findings and optimistic that they
will lead researchers in the directi
Contact: Carolyn Conway
Columbia University Medical Center