Major New Finding On Genetics Of Parkinson's Disease Zeroes In On Activity Of Alpha Synuclein

Public release date: 30-Oct-2003
Contact: Vicky Cahan
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301-496-1752
NIH/National Institute on Aging

Major new finding on genetics of Parkinson's disease zeroes in on activity of alpha synuclein.

Scientists investigating a rare familial form of early-onset Parkinson's disease have discovered that too much of a
normal form of the á-synuclein gene may cause Parkinson's disease. The finding, reported in the October 31, 2003, issue
of Science, shows that abnormal multiplication of the á-synuclein gene can cause the disease.

The study provides major new clues into the process by which Parkinson's disease develops. Further, it suggests another
way of looking at the consequences of abnormal protein deposition in a variety of neurological diseases, such as
Alzheimer's disease.

The Science findings are the product of collaboration among scientists at several institutions, including researchers
at the National Institutes of Health (NIH), part of the U.S. Department of Health and Human Services. They were
reported by Andrew Singleton, Ph.D., and colleagues at the National Institute on Aging's (NIA) Laboratory of
Neurogenetics, Matthew Farrer, Ph.D., of the Mayo Clinic, and Katrina Gwinn-Hardy, M.D., of the National Institute of
Neurological Disorders and Stroke (NINDS). The team also included scientists from the National Human Genome Research
Institute (NHGRI) and Georgetown University Medical Center, Washington, DC.

Until very recently, researchers focused on possible environmental factors as the culprit in Parkinson's disease.
However, in 1996, mutations in the á-synuclein gene were identified in a few large families in whom the disease was
unusually common. Since then, mutations in several other genes have also been linked to familial forms of Parkinson's
disease.

In this new study, investigators analyzed blood samples from another affected family, the "Iowa kindred," in which many
relatives developed Parkinson's disease or related neurological diseases. The family, followed by this team of
researchers for many years, presented a puzzle to scientists because the genetic analyses of some family members
initially showed no á-synuclein mutation. The scientists thought perhaps an entirely different genetic mutation might
account for Parkinson's disease in this family and had even given this other gene a name, PARK4.

Not satisfied that they had the answer, scientists on the team decided to look again at genetic samples from the
family, conducting additional analyses of the entire genome, including chromosome 4, the chromosome on which the á-
synuclein gene is located. In individuals in this family affected by Parkinson's disease, instead of the usual two
copies of the á-synuclein gene in the chromosome 4 pair, the researchers found four copies of the á-synuclein gene.
This multiplication of the á-synuclein gene (an abnormal triplication of three genes on one chromosome 4 and the normal
one copy on the other chromosome 4) results in the individual's having too much synuclein. This protein buildup is
believed to cause the Parkinson's disease symptoms.

"This study is an exciting step forward in our understanding of this disease," notes the NIA's Singleton. "It
contributes to the growing body of evidence suggesting that genetic variations in á-synuclein contribute to Parkinson's
disease. It suggests that in Parkinson's disease both mutated and normal á-synuclein behave in a way that is
quantitatively different from the way the protein functions in people without Parkinson's disease."

The researchers point out that the findings in the Science report are relevant to both familial and sporadic, or
typical, Parkinson's disease. The pathology of typical Parkinson's disease is similar to the pathology in this family,
they note, and previous work from the group and others has suggested that the amount of synuclein produced might
contribute to a person's risk of getting the disease. "We hope that this type of basic research will yield new
understandings that will ultimately allow us to go beyond just treating the symptoms of Parkinson's disease to one day
halting the disease's progression," says Farrer.

Further, the team notes, the mechanism of disease in this study is similar to that seen in people with Down syndrome,
where patients make an excess of a protein, beta-amyloid, which accumulates leading to a form of Alzheimer's disease.
This suggests that the same kind of disease mechanisms may be at work in a variety of diseases characterized by protein
accumulation in and around cells in the brain. The important new findings, the researchers emphasized, would not be
possible without the most critical partners in the research, the family members of the Iowa kindred. Some members of
the family have been involved with these research studies for many years, and many have devoted themselves to helping
researchers identify the cause of their disorder. The research team expressed deep appreciation for the family members'
participation and their patience. "The family was dedicated to the research even when it wasn't clear that we would
find the cause," says NINDS' Gwinn-Hardy, who has been studying the family for nearly a decade. "They have made many
sacrifices over the years to advance this work and their contribution needs to be recognized." The family, however, has
asked not to be contacted directly by the media.

Parkinson's disease is the second most common neurodegenerative disease, after Alzheimer's disease. It is estimated
that the disease currently affects at least 500,000 Americans. The disease occurs when nerve cells in an area of the
brain known as the substantia nigra die or become impaired. Normally, these neurons produce an important brain chemical
known as dopamine. The loss of dopamine-producing brain cells results in the four main symptoms of Parkinson's disease:
tremors, rigidity of the limbs, slowness of movement, and impaired balance and coordination.

###

More information on Parkinson's disease, Alzheimer's disease, genetics, and health and aging, is available from the
three NIH institutes collaborating in this study:

The NIA, which leads Federal efforts to support and conduct basic, clinical, epidemiological, and social research on
aging and the special needs of older people has information on Alzheimer's disease and aging, generally. Information on
memory and Alzheimer's disease can be viewed at the Web site http://www.alzheimers.org . Press releases, fact sheets,
and other materials about aging and aging research can be viewed at the NIA's general information Web site,
http://www.nia.nih.gov

The National Institute of Neurological Disorders and Stroke (NINDS), which leads Federal efforts to conduct and support
basic and clinical research on brain and nervous system disorders. More information about Parkinson's disease, the
Morris K. Udall Parkinson's Disease Research Centers of Excellence, and research on Parkinson's disease and other
neurological disorders can be viewed at the NINDS' general information Web site, http://www.ninds.nih.gov

The National Human Genome Research Institute (NHGRI) supports genetic and genomic research, investigation into the
ethical, legal and social implications surrounding genetics research, and related educational outreach activities. More
information about genetics research can be viewed at the NHGRI's general information Web site, http://www.genome.gov

The Mayo Foundation supports human medical research, including neuroscience and genetic research programs at Mayo
Clinic in Jacksonville. More information on these programs, Parkinson's disease and related disorders can be viewed at
the Mayo Web site, http://www.mayo.edu/fpd

Additional Contact:
NIA -- Vicky Cahan
301-496-1752

NINDS -- Marian Emr
301-496-5924

NHGRI -Larry Thompson
301-594-0954

Mayo Clinic -Erik Kaldor
904-953-2299

SOURCE: EurekAlert, DC
http://www.eurekalert.org/pub_releases/2003-10/nioa-mnf102703.php

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