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Duke Researchers Find Specific Genetic Link to Broad Spectrum of Parkinson's Disease Cases

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Duke Health News 919-660-1306

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 with mutations.

"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.

Duke team members include: Allison Rogala, Evadnie
Rampersaud, Jeffrey Stajich, Dr. Burton Scott, Robert Ribble,
Peggy Pate and Michael Booze. Other team members include: Dr.
Martha Nance, Struthers Parkinson's Center, Minn.; Dr. Ray
Watts, Emory University; Dr. Jean Hubble, Ohio State
University; Jonathan Haines and Dr. Thomas Davis, Vanderbilt
University; Drs. William Koller and Rajesh Pahwa, University of
Kansas; Drs. Matthew Stern and Amy Colcher, University of
Pennsylvania; Dr. Bradley Hiner, Marshfield Clinic, Wis.; Drs.
Joseph Jankovic and William Ondo, Baylor College of Medicine;
Dr. Fred Allen, Carolina Neurologic Clinic; Drs. Christopher
Goetz and Eric Pappert, Rush Presbyterian-St. Luke's Hospital;
Drs. Gary Small and Donna Masterman, University of
California-Los Angeles; and Nigel Laing and Dr. Frank
Mastaglia, University of Western Australia.

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