Parkinson's Disease Due to Extra Genes

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Parkinson's Disease Due to Extra Genes

Background: Parkinson's disease is, after Alzheimer's disease, the most common neurodegenerative disease. The four main symptoms of Parkinson's disease are tremors, rigidity of the limbs, slowness of movement, and impaired balance and coordination. Since 1997 it has been known that mutations in the gene encoding a protein called alpha-synuclein cause Parkinson's disease in certain families.

Summary: Four copies of the synuclein gene were found instead of the normal two in an Iowa family with hereditary Parkinson's disease. The two extra copies are due to an abnormal triplication of the synuclein gene on one chromosome. The result is too much synuclein. This protein buildup is believed to cause the Parkinson's disease.

Comment: Most common diseases are not simple, and Parkinson's disease is no exception. It is complex and has many different causes. It is hoped that all types of Parkinson's disease lead to the same final pathways, so that the same drugs may help all patients with Parkinson's disease. The accumulation of synuclein appears to be part of the final common pathway to Parkinson's disease.

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Barbara K. Hecht, Ph.D.
Frederick Hecht, M.D.
Medical Editors, MedicineNet.com


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 a-synuclein gene may cause Parkinson's disease. The finding, reported in the October 31, 2003, issue of Science, shows that abnormal multiplication of the a-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.

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Parkinson's Disease: Symptoms, Causes, Stages, Treatment

The Science findings 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 a-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 a-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 a-synuclein gene is located. In individuals in this family affected by Parkinson's disease, instead of the usual two copies of the a-synuclein gene in the chromosome 4 pair, the researchers found four copies of the a-synuclein gene. This multiplication of the a-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 a-synuclein contribute to Parkinson's disease. It suggests that in Parkinson's disease both mutated and normal a-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.

Source: National Institutes of Health, (www.nih.gov)


Quick GuideParkinson's Disease: Symptoms, Causes, Stages, Treatment

Parkinson's Disease: Symptoms, Causes, Stages, Treatment

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Reviewed on 7/8/2004

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