Genetic Risk Factor For Parkinson's Disease Discovered

DURHAM, N.C. -- Inherited variations in proteins that produce energy
for the body may provide protection from developing Parkinson's
disease, according to a new study by scientists at Duke University
Medical Center.

Furthermore, the inherited gene variations seem particularly to
protect white women, which may help explain why Parkinson's disease
is seen more often in men.

The study, published in the April issue of the American Journal of
Human Genetics and available on-line at the journal's Web site
(http:// www.journals.uchicago.edu/AJHG/journal/issues/v72n4/024579/
024579.html) is the first to assign specific genetic risk factors to
the most common form of Parkinson's disease, which affects more than
1 million people in the United States.

The genetic risk factors for Parkinson's disease have been difficult
to study because it is a complex disease that likely has both genetic
and environmental components, said Jeffery Vance, M.D., lead author
of the study. "We are finding that Parkinson's disease is not one
disease; it is many diseases," he added.

The disease itself is a degenerative disorder of the portion of the
brain that controls movement. Progressive nerve degeneration results
in difficulty initiating movements such as walking, a loss of
balance, rigidity and tremor.

Recent scientific studies had shown that people affected by
Parkinson's disease have defects in mitochondria, the cellular
components that produce energy for the body. Studies in rats have
shown that chronic exposure to the common pesticide rotenone can
cause damage to the energy producing proteins in the mitochondria and
induce symptoms that mimic Parkinson's disease in people. These
proteins, which together are called complex I, are among the few
genes encoded in the genetic material of the mitochondria itself.

"Mitochondria have been implicated in Parkinson's disease, but no one
really understood why," said Vance, an associate professor of
medicine at Duke.

Vance and his colleagues decided to examine whether common gene
variations called haplogroups that exist in the complex I proteins
could change a person's susceptibility to developing Parkinson's
disease.

The scientists examined the mitochondrial DNA of 609 Parkinson's
disease patients and 340 normal controls who had no signs of the
disease. In particular, they looked at nine well-known and well-
studied gene variations that vary among ethnic groups. When they
looked at the correlation between gene variation and incidence of
Parkinson's disease, they discovered that one variant, called "J" was
much more common in people who do not have Parkinson's disease, and
particularly among women.

"The J haplogroup is much more common in unaffected individuals, so
that would suggest it is protective," said Vance.

The J variant is found in about 26 percent of Caucasians, versus two-
thirds of Asians and more than 90 percent of sub-Saharan Africans.
However, the researchers noted that since they only studied
Caucasians in this study, they could venture no conclusion about
whether the J variant is protective in other ethnic groups.

"It is interesting, however, that this protective allele is more
common in the groups that are thought to have a lower incidence of
Parkinson disease," said Vance, adding that further research should
help clarify the gene's protective effect.

The other gene variations studied showed no statistical variation
among groups.

The scientists speculate that the J variant, which produces a protein
differing by only one protein building block, turning the amino acid
threonine into an alanine, may change its function slightly. The
result, they say, could affect one's ability to process damaging
oxygen free radicals that are a side effect of energy production.
People carrying the J variant may be better prepared to handle
oxidative stress than people carrying other variants.

"One of the mechanisms proposed to be responsible for degeneration of
neurons involved in Parkinson's disease is excessive oxidative stress
over time," said Vance. "The toxic effects resulting from excess
oxygen damage, combined with exposure to pesticides such as rotenone,
could act synergistically to cause Parkinson's disease. This is the
first study to give substance to the idea."

Additional studies will be needed to further examine the link between
variant J and Parkinson's disease, said Vance. Given the complex
nature of the disease, the apparent protective effect of the J
variant will need to be examined in other groups, and additional
genetic and biochemical studies will be needed.

Joelle van der Walt, Kristin Nicodemis, Eden Martin, Ph.D., William
Scott, Jeffrey Stajich, Adam McLaurin, Burton Scott, M.D., Donald
Schmechel M.D., and Margaret Pericak-Vance, Ph.D., all of Duke, also
contributed to the study, as did researchers from 14 additional
medical centers across the United States.

The research was supported by a program project grant from the
National Institutes of Health, and grants from the National Institute
on Aging, the McKnight Foundation, GlaxoSmithKline, Inc. van der Walt
is supported by a fellowship from the American Parkinson's Disease
Foundation.

Note: This story has been adapted from a news release issued for
journalists and other members of the public. If you wish to quote any
part of this story, please credit Duke University Medical Center as
the original source. You may also wish to include the following link
in any citation:

http://www.sciencedaily.com/releases/2003/04/030407075220.htm

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