Huntington's Disease Findings Pave Way For Potential Cure

August 08, 1997

New York, N.Y., August 8, 1997- Nearly 20 years ago, Columbia University researchers observed brain cell changes in Huntington's disease patients. Today, the significance of those changes has finally been explained--and the new findings may lead to a treatment or cure for the progressive, degenerative brain disease.

In the August 7 issue of Cell, Dr. Gillian Bates of the Division of Medical and Molecular Genetics, Guy's Hospital, London; Dr. Stephen W. Davies of the Department of Anatomy and Developmental Biology, University College London; Dr. Hans Lehrach and Dr. Erich Wanker of the Max Planck Institute for Molecular Genetics in Berlin, and colleagues have described the changes with unprecedented clarity. The cellular and biochemical mechanisms they have discovered could be a starting point for the development of new drugs that could interrupt the progress of Huntington's disease or prevent it in people at risk.

The gene for Huntington's disease (HD) was discovered in 1993 through the collaborative efforts of six research teams led by Nancy S. Wexler, PhD, Higgins Professor of Clinical Neuropsychology at the College of Physicians and Surgeons of Columbia University in New York and President of the Hereditary Disease Foundation in Santa Monica. Under the direction of Wexler, the Foundation has formed the Cure Huntington's Disease Initiative to accelerate progress from research to therapy.

Symptoms of Huntington's disease include abnormal movements, moodiness, depression, slurring and loss of speech, and, finally, mental incompetence, incontinence, confinement, and unremitting decline over 10 to 20 years. This progressive degenerative brain disease affects about 30,000 Americans; 150,000 more have a genetic risk for developing the illness. The cause is a mutation in a gene located on chromosome 4: Instead of having molecule groups that repeat a small number of times, they repeat 40 or more times and produce a defective form of the huntingtin protein. The defective protein interacts with brain cells, though exactly how has not been known.

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 direction of an effective treatment. At the moment, a blood test can detect the HD gene, but there is no cure and no effective treatment. In a second study in the current issue of Cell, an international group led by Eberhard Scherzinger of the Max Planck Institute announce that they have found a way to recreate the protein clumps in a test tube, which will make it much easier to develop new therapies that prevent the clumping. The Bates research was supported in part by the Hereditary Disease Foundation. Founded by Dr. Wexler's father, Milton Wexler, the foundation's goal is to provide intellectual stimulus and financial support for basic scientific research aimed at uncovering the causes of Huntington's disease and related genetic and neurological disorders. The Hereditary Disease Foundation also seeks to advance the treatment of these incurable and devastating illnesses. The foundation's Cure Huntington's Disease Initiative will support further research into medications effective in treating HD.

Columbia University Medical Center

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