BETHESDA, Md. - Scientists at the National Human Genome Research Institute (NHGRI) at the National Institutes of Health (NIH) have for the first time precisely identified a gene abnormality that causes some cases of Parkinson's disease. The gene spells out instructions for a protein called alpha synuclein. In the abnormal version of the gene, the researchers found a mutation in a single base pair - one incorrect letter in the string of more than 400 that compose the instructions for making the protein. Because the normal gene plays a role in the function of nerve cells, the finding gives researchers a powerful new tool for understanding cellular abnormalities in Parkinson's disease and demonstrates a connection between Parkinson's disease research and research into other neurological disorders, such as Alzheimer's disease.
The research report appears in the June 27 issue of the journal Science.
According to NHGRI's Dr. Mihael Polymeropoulos, the paper's lead author, "the finding opens completely new horizons in understanding the disease and interpreting the biology of the illness. Moreover, the finding will have an application in the not too distant future as a clinical research tool within families especially prone to Parkinson's disease and may permit us to design clinical studies for investigating drugs or other ways of postponing or offering protection from the illness."
The paper confirms last fall's report - co-authored by the same NHGRI team - that a predisposition to at least one form of Parkinson's disease is inherited and that the gene responsible was situated somewhere in a large region on the long arm of chromosome 4. Until that report, most experts believed that Parkinson's disease was probably due to unknown factors present in the environment.
Parkinson's disease afflicts about a 500,000 people in the United States alone, with about 50,000 new cases reported every year. Its hallmark is shaking or trembling of a limb and, in the later stages, a slow, shuffling walk and stooped posture.
Parkinson's disease is a common progressive neurological disorder that results from loss of nerve cells in a region of the brain that controls movement. This degeneration creates a shortage of the brain signaling chemical - dopamine - causing impaired movement. When symptoms grow severe, doctors usually prescribe levodopa (L-dopa), which helps replace the brain's dopamine.
"This finding could prove to be the most significant advance in our understanding of Parkinson's disease since the dopamine hypothesis was put forward in the mid 1960s. It is a good example of how we make progress towards the conquest of particular diseases by supporting a diversity of fundamental and clinical research. This discovery about Parkinson's disease also deepens our study of Alzheimer's disease, basic neuroscience, cell biology, and genome research and gene mapping," said NIH Director, Dr. Harold Varmus.
To find the gene, the scientists first studied members of a large family that came originally from Italy. Some had emigrated to the US early in this century, and more than 60 family members on both sides of the Atlantic have been diagnosed with Parkinson's disease. Efforts to locate the gene intensified after a workshop on Parkinson's disease sponsored by the National Institute of Neurological Disorders and Stroke (NINDS). At that meeting, which identified genetic research as an important area of opportunity, scientists from NIH met researchers at the University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School in Piscataway, New Jersey, who had been investigating Parkinson's prone families for some time. Soon after, the NIH scientists, led by Dr. Polymeropoulos, began to carry out a genetic analysis of Parkinson's disease using DNA from patients identified and followed by an international team of researchers, including the Robert Wood Johnson team and physicians at the University of Naples, Italy. With the help of collaborators at the University of Patras Medical School in Greece, the NHGRI researchers also studied five additional unrelated families of Greek origin with a hereditary form of the disease.
Using information provided by the Human Genome Project (HGP), NHGRI researchers rapidly located the mutation to a region of the genome containing approximately 100 genes. One of the genes already placed in this interval was alpha synuclein. The alpha synuclein gene was an excellent candidate for being a Parkinson's disease gene because previous research had already shown that the amyloid plaques of Alzheimer's disease patients contained fragments of the alpha synuclein protein. Considering its potential role in neurodegenerative disease, the researchers began looking at the precise sequence of alpha synuclein in normal and affected individuals. In the Italian family and three of the Greek families, the Parkinson's patients were found to possess an identical mutation in a single base pair of the alpha synuclein gene.
Parkinson's disease is characterized by deposits in the brain called Lewy bodies. The researchers hypothesize the mutation in the synuclein protein causes it to aggregate, thus attracting other proteins to form a deposit that damages the cell. A similar mechanism has been proposed for the production of amyloid plaques in Alzheimer's disease. The finding that Alzheimer's disease plaques contain a fragment of alpha synuclein further strengthens the idea that a common mechanism may be operating in both of these neurodegenerative diseases.
The NHGRI researchers suspect that the abnormal gene is responsible for a significant portion of familial Parkinson's disease with onset generally before the age of 60. It is not known how frequent alterations in this gene will be in later onset cases with less striking family history, though the same pathway which has been identified to be involved in these four families may turn out to be abnormal in other patients as well. Alpha synuclein is actually a member of a group of similar synuclein genes in the human genome. The NHGRI scientists are now actively searching among patients with familial Parkinson's disease who do not possess this alpha synuclein mutation for mutations in those other synuclein genes. The alpha synuclein gene, and other similar genes known to exist in the human genome, are expected to help scientists decipher additional causes of Parkinson's and perhaps shed light on other devastating and common brain disorders.
"For people with Parkinson's disease, this is a small but important step in a very long journey - hopefully leading to an understanding of the basic underlying defect in Parkinson's disease which causes the death or loss of function of the cells in the brain. If it results in a deeper understanding of how Parkinson's disease comes about, it may make us much smarter in developing therapies. But it is important to stress that at this point there is no direct therapeutic result from this finding," said the paper's senior author, NHGRI's Dr. Robert Nussbaum.
Although the researchers caution that a test will provide limited information for most people, one near-term application for such a test in high-risk families will be in research aimed at developing ways of slowing or stabilizing the illness. Investigators are hoping that such preventive measures will eventually be useful in treating Parkinson's disease.
The discovery of the mutant alpha synuclein gene raises issues of genetic testing that have become increasingly familiar as the list of gene discoveries lengthens. The issues are especially similar to those that have arisen in connection with genetic testing for predisposition to other diseases that appear late in life, notably Alzheimer's disease and Huntington's disease.
"Discoveries like this reflect how rapid disease gene identification can be as the Human Genome Project has continued to mine the genome for its treasures," says NHGRI Director Dr. Francis Collins. "As more gene sites are identified, it will become almost routine for disease gene hunters to find an already characterized gene waiting for them when they arrive at the neighborhood they know is involved in a disease. But this discovery, which raises the possibility of identifying healthy individuals at future risk for illness, also underlines again how crucial it is they provide legislative protections against misuse of the information, especially in health insurance and employment."
"The results announced today highlight the importance-and benefit-of bringing new ideas into the field of Parkinson's disease research," says Dr. Zach W. Hall, Director of the NINDS. "The identity of this gene suggests an important new link between Parkinson's and Alzheimer's diseases, and may ultimately help us prevent or delay the cell death that is responsible for degenerative brain disease."
NHGRI oversees the NIH's role in the Human Genome Project, an international research effort to develop tools for gene discovery.
Last Updated: March 22, 2012