EMBARGOED FOR RELEASE: 5 OCTOBER 2000 AT  10:00 ET US
Contact: Richard Merritt
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Duke University Medical Center

Duke researchers find specific genetic link to broad spectrum
of Parkinson's disease cases

PHILADELPHIA  --  Parkinson's disease researchers at Duke University
Medical Center have demonstrated for the first time that alteration
of a specific gene on chromosome 6 appears to contribute to both the
common late-onset form of Parkinson's disease, and the rarer,
early-onset form of the disease.

In 1998, Japanese researchers reported that mutation of this gene,
which they dubbed "Parkin," was responsible for autosomal recessive
juvenile parkinsonism, a disorder similar to, but considered distinct
from, Parkinson's disease (PD).  Mutations in the Parkin gene were
found in a small group of Japanese with autosomal recessive juvenile
parkinsonism.

The Duke researchers, applying the latest genetic sleuthing techniques
to a much larger and more diverse group of families with PD, were able
to find a small and previously undiscovered mutation on exon 3 of the
Parkin gene, suggesting there may be a genetic link to the various
manifestations of the disease.

"The findings demonstrate for the first time a common genetic basis
for the different forms of Parkinson's disease, and they suggest that
the Parkin gene might eventually be a useful diagnostic tool for the
disease," said Duke genetic epidemiologist William Scott, who prepared
the results of the Duke team's study for presentation Thursday at the
annual scientific sessions of the American Society for Human Genetics.

"As little as five years ago, it was thought that Parkinson's disease
was caused solely by environment factors, and that there wasn't a
genetic component," said Margaret Pericak-Vance, director of Duke's
Center for Human Genetics (CHG) and one of the principal investigators
of Duke's PD research efforts.  "In a relatively short period of time,
we have been able to show that genetics plays an important role in a
patient's susceptibility to the disease."

The study was funded by Glaxo Wellcome, the Deane Laboratory for
Parkinson's Disease Research and the Duke CHG.  The other Duke PD
principal investigator, Dr. Jeffery Vance, director of the Genomics
Research Laboratories at CHG, directs and is funded by the
Morris K. Udall Parkinson Center of Excellence, one of eight federally
funded institutions nationwide studying PD.

The discovery of the Parkin mutation marks the second gene implicated
in PD.  In 1997, researchers from Europe found a connection between
the alpha-synuclein gene on chromosome 4 and small number of early
onset cases of PD in Europe.  However, the Duke researchers say, a
genetic link to the late onset, and most common form of the disease,
had not been made.

"The significance of the Parkin discovery is that it appears to be
a causative gene, and it shows up fairly frequently across the
spectrum of age of onset," Vance said.  "Now we have two genes that
are involved in the disease, and we don't know yet if or how they
might interact with each other.  Parkinson's disease is a complex
disorder, which has a combination of genetic and environmental
factors and is probably caused by a mixture of mutations and
susceptibility factors."

The Duke researchers lead a team from 13 institutions across the
United States and Australia who have been searching for families
with one or more members with PD.  The researchers identify families,
produce detailed pedigrees of each family, collect blood samples from
as many members as possible and conduct sophisticated genetic analyses
to spot any common genetic mutations that might confer susceptibility
the disease.

To date, the team has collected data on more than 175 such families
(864 individuals).  Unlike the original Japanese and European studies,
which focused on specific subgroups of PD patients, the families in
the Duke analysis came from a broad spectrum of geographical locations,
ethnicity and age of onset.

Using this approach, the Duke researchers found the previously
undiscovered exon 3 deletion in 41 percent of the families.
"We took a different approach by looking at a wide range of people
with Parkinson's disease, and we were able to find this genetic
mutation," Vance said.  He added that the team used a system known
as denaturing high pressure liquid chromatography, which is much
more sensitive in detecting smaller and more subtle genetic
abnormalities than other screening techniques.

The next hurdle facing researchers is determining the function
of the protein produced by the Parkin gene.  It is thought that
the Parkin protein works in combination with another protein,
ubiquitin, and together they act as a sort of waste-hauling system,
ridding the cell of normal metabolic byproducts.

PD affects a portion of the brain known as the substantia nigra,
which is responsible for movement.  When the substantia nigra
of a PD patient is autopsied, pathologists typically find plaques
in the brain cells known as Lewys bodies, and it may be possible
that buildup of cellular waste products leads to their development.

The symptoms of PD – tremors, muscle stiffness and slowness of
movement – can vary from patient to patient.  The mainstay of PD
treatment is the administration of the drug L-dopa, which when it
enters the central nervous system, is converted into the
neurotransmitter dopamine, which is found in reduced quantities
in PD patients.  However, the effectiveness of the drug to treat
symptoms decreases over time and increased doses lead to unwanted
side effects.

The identification of the protein produced by the Parkin gene
should give researchers a molecular target at which to aim
therapeutic agents, Scott said.

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http://www.eurekalert.org/releases/dumc-drf100300.html