By Sean Henahan, Access Excellence

Caption: NHGRI graphic shows DNA in action

Scientists at the National Human Genome Research Institute (NHGRI) have identified a gene that encodes a protein called alpha synuclein. Studies of an abnormal version of the gene revealed a mutation in a single base   pair. 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.

"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," said the NHGRI's Dr. Mihael Polymeropoulos.

The paper confirms an earlier report by the same research group of an Italian family with a genetic predisposition to one form of Parkinson's disease. That study  showed that the gene responsible was situated somewhere in a large region on the long arm of chromosome 4. Until that report, the consensus was that environmental toxins were the primary cause Parkinson's disease.

"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," says NIH director, Dr. Harold Varmus.

The new data also comes from studies 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. The researchers also studied five additional unrelated families of Greek origin with a hereditary form of the disease.

Using data obtained through the Human Genome Project, the 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 distinguished 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 believe that the abnormal gene is responsible for a significant portion of familial Parkinson's disease with onset generally before the age of 60. It remains to be seen whether these alterations will also be involved in other forms of the disease with later onset and less familial history. The researchers are now looking at related synuclein genes among patients with a familial history of Parkinson's disease but no defect in the alpha synuclein gene.

"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 in 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," says the NHGRI's Dr. Robert Nussbaum.

The fact that alpha synuclein appears to play a role in both Parkinson's disease and Alzheimer's disease will prove valuable to researchers looking at both diseases.

"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."

The discovery of  a gene indicating a predisposition to a chronic degenerative disease also highlights issues in genetic testing similar to those seen with 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 the provide legislative protections against misuse of the information, especially in health insurance and employment."

The research appears in the June 27, 1997 issue of the journal Science.

Parkinson's disease was first described in 1817 by the English physician James Parkinson as the "shaking palsy". This common chronic progressive disorder of late adult life manifests as tremors of the hands, muscular rigidity, slowness of movement and a stooped posture and shuffling gait.

About 50,000 Americans are diagnosed with the disease each year. This is a mysterious disease with no known cause or cure. The cause of Parkinson's disease is currently thought to be a combination of environmental and genetic factors.

The first treatment breakthrough came with levadopa. The drug essentially replaces the lost dopamine in the brain. However, large doses are required, resulting in undesirable side effects, such as nausea, heart problems & dementia. The subsequent development of carbidopa, which is given in conjunction with levadopa, allows a smaller dose of levadopa to be used, resulting in fewer side effects.

Many patients respond well at first to this combination therapy, but after a couple years of treatment the effects may begin to wear off. At the same time, prolonged use of levadopa can have serious side effects including involuntary movements of the limbs and psychological disturbances.

A new treatment called seligiline has recently become available which has a completely different mechanism of action from levadopa. The drug is potent inhibitor of an enzyme called 'monoamine oxidase B' which breaks down dopamine. This means more dopamine can be preserved in the brain. The drug appears to have a neuroprotective effect and may delay the onset of Parkinson's symptoms.