Scientists investigating a rare familial form of early-
onset Parkinson's disease have discovered that too much of
a normal form of the alpha-synuclein gene may cause
Parkinson's disease. The finding, reported in the October
31, 2003, issue of "Science", shows that abnormal multiplication of the alpha-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 alpha-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 alpha-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 alpha-synuclein gene is located. In individuals in this family affected by Parkinson's disease, instead of the usual two copies of the ·alpha-synuclein gene in the chromosome 4 pair, the researchers found four copies of the alpha-synuclein gene. This multiplication of the alpha- 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 alpha-synuclein contribute to Parkinson's disease. It suggests that in Parkinson's disease both mutated and normal alpha-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 . Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information Web site, .

— 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, .

— 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, .

— 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, .

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