Columbia University Medical Center and Albert Einstein College of Medicine researchers have identified a possible cause of an inherited form of Parkinson's disease, which may be related to more common forms of the disease. The findings are reported in the August 27, 2004 issue of Science.
While the cause of most cases of Parkinson's disease is unknown, a few cases are inherited and can be traced to mutations in four different genes, including the alpha-synuclein gene. This is the first study that may pinpoint the mechanism by which the mutant gene initiates a cascade of events that causes this devastating neurological disease.
"This discovery could aid in the development of new, targeted treatments to slow or stop the disease progression," said David Sulzer, Ph.D., professor of neurology and psychiatry at Columbia University College of Physicians and Surgeons and senior author of the study. "This is an extension of the genetic research that discovered the mutant alpha-synuclein gene and it is exciting to see how this information can be used to possibly determine the cause of Parkinson's disease."
Blockage Causes Neuron Death
Neurons that release dopamine, the neurotransmitter that controls coordinated movement, slowly die in people with Parkinson's disease, causing progressively more limited mobility and speech. Results of the new research indicate that in patients with a mutant alpha-synuclein gene, Parkinson's disease may be caused by a blockage within dopamine neurons.
In the study, the mutant forms of alpha-synuclein protein was shown to bind to protein disposal sites within dopamine neurons. This creates a blockage that leads to the eventual death of the neurons. The study was conducted in dopamine neurons taken from mice.
Dr. Sulzer likens the situation to a garbage truck stalling at the entrance to the town dump. "If the truck breaks down right in front of the dump, not only does it fail to deliver its own garbage to the dump, but it blocks all the other garbage trucks and the town fills up with garbage," said Dr. Sulzer.
Together with Ana Maria Cuervo, M.D., Ph.D., assistant professor of anatomy and structural biology at Albert Einstein College of Medicine and the study's lead author, Dr. Sulzer is now using the study's findings to examine whether a backup at the protein disposal sites also plays a key role in the most common idiopathic form of Parkinson's, which has no known cause.
"These patients do not carry a mutant alpha-synuclein gene, but their alpha-synuclein proteins bear modifications not seen in healthy people that may cause the protein to act as the mutant does," said Dr. Sulzer.
The research was supported by the National Institutes of Health, a National Institute of Neurological Disorders and Stroke Udall Center Grant, the Parkinson's Disease Foundation, the Lowenstein Foundation, the Matheson foundation, the Huntington's Disease Society of American and the Howard Hughes Medical Institute.
Leonidas Stefanis, M.D., Ph.D., assistant professor of neurology at Columbia University Medical Center, and Harvard researchers Ross Fredenburg and Peter T. Lansbury, Ph.D., associate professor of neurology, also participated in the research.
Located in New York City, Columbia University Medical Center provides international leadership in basic and clinical research, medical education, and health care. The medical center includes the dedicated work of many physicians, scientists, and other health professionals at the College of Physicians & Surgeons, the School of Dental & Oral Surgery, the School of Nursing, the Mailman School of Public Health, the biomedical departments of the Graduate School of Arts and Sciences, and allied research centers and institutions. The pioneering tradition of Columbia University health scientists, who have achieved some of the 20th century's most significant medical breakthroughs, continues today.
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