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 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.
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.
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.
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
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.
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
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.
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
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.
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."
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
NHGRI oversees the
NIH's role in the Human Genome Project, an international
research effort to develop tools for gene discovery.
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
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.