Source: NIH

A GENE FOR PARKINSON'S DISEASE

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 anywhere from 1 to 1.5 million Americans.

The findings are reported by National Institutes of Health (NIH) scientists
from the National Center for Human Genome Research (NCHGR) 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," says 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 form NCHGR and NINDS met
Roger Duvoisin, M.D., of UMDNJ-Robert Wood Johnson Medical School. Soon
after, the NIH scientists, led by Michael Polymeropoulos, M.D., of NCHGR,
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," says 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," says 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 Duboisin 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," says 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," says 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," says Robert Nussbaum, M.D., Chief of NCHGR'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 Ubel, 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 NCHGR 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.

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