BETHESDA, Md. - For the first time, scientists have pinpointed the location of a gene they believe is responsible for some cases of Parkinson's disease. Their discovery provides strong evidence that a genetic alteration is capable of causing the disease. The study, published in the November 15 issue of Science, sheds light on the mysterious origins of this devastating neurological disease that affects at least 500,000 Americans.
The findings are reported by National Institutes of Health (NIH) scientists from the National Human Genome Research Institute (NHGRI) and the National Institute of Neurological Disorders and Stroke (NINDS), in collaboration with researchers from the UMDNJ-Robert Wood Johnson Medical School in New Brunswick, New Jersey, and the Istituto de Scienze Neurologiche in Naples, Italy.
"This exciting result gives us a powerful new tool to understand why nerve cells die in Parkinson's disease and how to stop them from dying. It will usher in a new era of Parkinson's disease research," said NINDS Director Zach Hall, Ph.D.
Efforts to locate the gene intensified after an August 1995 NIH-sponsored workshop on Parkinson's disease at which scientists from NHGRI and NINDS met Roger Duvoisin, M.D., of UMDNJ-Robert Wood Johnson Medical School. Soon after, the NIH scientists, led by Mihael Polymeropoulos, M.D., of NHGRI, began to carry out a genetic analysis of Parkinson's disease using DNA from patients identified and followed by an international team led by Dr. Duvoisin.
The impact of the current finding is to show that a single gene alteration can cause the disease. The next step will be to find and identify the specific gene involved, which is located somewhere within a region of DNA on the long arm of chromosome 4. Learning the gene's exact location and isolating it may eventually lead to genetic testing that will help early diagnosis and treatment. Learning what the gene is and how it works may help researchers design treatments for all forms of Parkinson's disease - not only inherited cases, but also those with no familial link.
"We don't know that this gene affects all people with Parkinson's disease, since we've only found it in one family," said Dr. Duvoisin. "But this is a very important step. We now know what we have to do to understand what causes the disease."
Until recently, most scientists believed the disease was due almost exclusively to environmental factors such as drugs or toxic chemicals, although in most cases, no environmental cause has been identified. But many people appear to have an inherited susceptibility to the disease. Studying a causative gene will help researchers discover how the disease occurs and how to develop methods of preventing or curing the disease.
"Mutations in the gene located in this region will cause classical Parkinson's disease, the very same symptoms commonly found in most people with Parkinson's," said Dr. Polymeropoulos, lead author of the report. "Understanding how that happens will help fit all the pieces of this complicated disease together."
The researchers identified the gene region by studying the DNA of 28 members of a large Italian family containing almost 600 people. People in this family, some of whom migrated to the United States between 1890 and 1920, can trace their ancestry to a single couple who lived in Italy in the 18th century. More than 60 family members on both sides of the Atlantic have been diagnosed with Parkinson's disease.
Dr. Duvoisin and his colleagues have studied the inheritance patterns of Parkinson's disease for decades. In the 1980's, they began studying families with multiple cases of the disease. They have now defined the pattern of inheritance in 80 multicase families.
"Information on inheritance patterns of the disease opened the door to an aggressive approach to understanding the genetics using the gene-finding tools of the Human Genome Project," said Dr. Polymeropoulos. "Once we started studying DNA from the families, we were able to map the gene in a matter of weeks. Past disease-gene hunts have taken anywhere from years to decades."
The gene mutation in this family is inherited in a dominant fashion, meaning that people who possess the mutation have a 50 percent chance of passing it on to their children. Only one parent must carry the mutation for the disease to appear in a couple's offspring. The symptoms of familial Parkinson's are identical to those in families with no history of the disease, except that the inherited form sometimes develops earlier in life.
Symptoms of Parkinson's disease include tremor (particularly tremor of a body part at rest), stiff limbs, slow or absent movement, lack of facial expression, a shuffling gait, and a distinctive stoop. Other symptoms, such as depression and impaired ability to think may also develop, especially during the later stages of the disease. These symptoms result from degeneration of nerve cells in the brain. The withered cells fail to release dopamine, one of the neurotransmitters, or nerve signaling chemicals, crucial for communication between nerve cells.
To learn what percentage of Parkinson's disease patients possess an alteration in the chromosome 4 gene, Dr. Polymeropoulos and his colleagues plan to study additional families with several affected individuals to see if they carry the distinctive marker in the same region on chromosome 4. Although many families have more than one member with Parkinson's disease, "there are not very many of the size of the family that we used, so it may be a question that will take some time to answer," said Dr. Polymeropoulos. Families with different inheritance patterns may have mutations that are different from the one found in the Italian family.
"Even with a relatively common disease like Parkinson's, it is rare to find families or situations that give us such particular insight and research power," said Robert Nussbaum, M.D., chief of NHGRI's Laboratory of Genetic Disease Research. "We need the help of the public, as well as physicians who are out there taking care of those patients, to keep their eyes open for these unusual situations which can be so helpful in furthering our research."
The long list of people with Parkinson's disease includes evangelist Billy Graham, science journalist Earl Ubell, and Attorney General Janet Reno. Many other people, including the former boxer Muhammed Ali, have Parkinson's-like symptoms due to head injury, toxic chemicals, or other problems. Another Parkinson's-like disorder, Wilhelmsen-Lynch disease (disinhibition-dementia-parkinsonian-amyotrophy complex), has been linked to a region of chromosome 17. A defect in mitochondrial DNA, which is separate from a person's chromosomes, was recently linked to sporadic Parkinson's disease with unusual symptoms. Other genetic mutations may also play a role in some cases.
The NHGRI oversees NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery. The NINDS is the nation's leading supporter of research on the brain and nervous system and a lead agency for the Congressionally-designated Decade of the Brain.
Last Updated: February 25, 2012