Oct. 6, 2000 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.
"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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