EMBARGOED FOR RELEASE
Thursday, June 26, 1997
4:00 PM Eastern Time
Jeff Witherly/Galen Perry, NCHGR
(301) 402-8564
Sharon Durham/Leslie Fink, NCHGR
(301) 402-0911
Marian Emr, NINDS
(301) 496-5924



NIH Researchers Find First Parkinson's Disease Gene




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," says 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, 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," says 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 the 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.


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Press contact information:

For interviews with Drs. Mihael Polymeropoulos or Robert Nussbaum of the
National Human Genome Research Institute, contact Jeff Witherly or Galen
Perry at (301) 402-8564 or -3035.


For interviews with Dr. Francis Collins, Director of the National Human
Genome Research Institute, contact Sharon Durham or Leslie Fink at (301)
402-0911.


For interviews with Dr. Zach Hall, Director of the National Institute of
Neurological Disorders and Stroke; Parkinson's patients or Parkinson's
support group, contact Marian Emr at (301) 496-5924.

The NHGRI website is located at: http://www.nhgri.nih.gov/

The NHGRI website will carry the press conference in audio form at 4 p.m.,
June 26th. The website will also have additional information on the
research, research teams, prior Parkinson's disease research announcements,
related links and public and media information on genetic research, genetic
testing and the Human Genome Project. For broadcast media, downloadable
broadcast quality AIFF. Electronic media will receive laboratory B-roll at
the press conference which includes explanatory statements on the finding
by Drs. Polymeropoulos and Nussbaum.

NHGRI will also uplink B-roll by satellite starting at 1:00 p.m. -- under
embargo restrictions-- for electronic teams unable to make the trek to
Washington.

There will be a press conference beginning at 1:00 p.m. on Thursday, June
26, in the First Amendment Room of the National Press Club, 14th and F
Streets, NW, Washington, D.C. Jim Cordy
Pittsburgh
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