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Genes and Parkinson’s
Recent findings hint at genetic role in Parkinson’s in older patients
By Marlene Cimons

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When Parkinson's disease was first recognized as a neurological disorder in the 1920s, researchers devoted scant attention to the idea that it might have genetic underpinnings. The thinking then—and for decades to follow—was that the environment was primarily to blame.

Parkinson's disease involves decreased levels of dopamine in certain areas of the brain. PET images show differences in F-DOPA levels between a Parkinson patient's brain (right) and a control (left).

This view began to change in 1996 when a team of scientists unraveled the DNA of an Italian family to find a genetic link to Parkinson's, albeit the rare early-onset kind. Now there is evidence tying genes to late-onset Parkinson's, which accounts for the majority of cases.

‘The genetic approach is a powerful addition to current research methods.’

Two studies released in recent weeks from researchers at Duke University in Durham, North Carolina, and one from Decode genetics in Reykjavik, Iceland, provide tantalizing new clues that bolster the importance of genes in Parkinson's that develops later in life, usually after age 65. Indeed, if these latest leads are confirmed, they could prompt new avenues of research into this devastating disorder that afflicts millions of individuals worldwide.

The result would not necessarily rule out environmental influences, although new data could significantly shift the balance between researchers' understanding of environmental factors and the roles played by genes.

"The genetic approach is not a replacement for other research methods; it's a powerful addition to current research methods," says Robert Nussbaum, chief of the genetic disease research branch at the US National Human Genome Research Institute in Bethesda, Maryland. "I think there is more and more evidence accumulating that there are genetic contributions, probably in the area of predisposition." Nussbaum, who studies the genetics of Parkinson's adds, "If we can identify what the predisposing genes are, and the pathways that these genes control, it'll make us smarter in figuring out what the environmental factors are."

"If we find that a genetic predisposition involves a pathway that detoxifies certain chemicals—then, obviously, those chemicals would be interesting things to look at," Nussbaum says.

In one of two the studies released by Duke and published in the November 13 issue of The Journal of the American Medical Association, a team of researchers from 16 institutions across the United States and Australia identified 174 families with one or more members who have Parkinson's. They collected blood samples from as many of them as possible and conducted genetic analysis, seeking to find common genetic factors that might indicate a susceptibility to Parkinson's. Margaret Pericak-Vance, director of Duke's Center for Human Genetics, led the study.

Of the 870 family members studied, 378 had diagnosed Parkinson's, 379 were unaffected, and the clinical status of the rest was unclear.

The Duke researchers saw evidence of genetic linkage to five distinct regions on chromosomes 5, 6, 8, 9, and 17. Chromosome 6 contains the Parkin gene, previously thought to be involved only in the rare early-onset form of the disease. But the researchers discovered Parkin mutations in 18 families with both late- and early-onset cases, including 11 early-onset and 7 late-onset families.

Parkinson's disease was first described in 1817 by James Parkinson in a paper entitled "An Essay on the Shaking Palsy."

In families with late-onset Parkinson's, the strongest overall evidence for linkage was on chromosome 17, near the tau gene, which has been implicated in other degenerative neurological diseases, such as Alzheimer's disease. Previously, tau has not been thought to be involved in the most common form of Parkinson's. Tau is a protein that helps maintain brain cell structure.

In the second Duke study, led by Jeffrey Vance, researchers analyzed the blood of 1,056 people with at least one afflicted individual in the family. They found evidence that three genetic variations in the tau gene seem to make some people susceptible to developing late-onset Parkinson's.

The Decode researchers, who presented their findings in October at the American Society for Human Genetics meeting in San Diego, said they had successfully mapped a gene contributing to late-onset Parkinson's to a small region on chromosome 1. They analyzed genotypic data from 51 families, including individuals with late-onset Parkinson's and their unaffected relatives.

Earlier, in December 2000, Decode scientists wrote in The New England Journal of Medicine about a role for genetic factors in Parkinson's suggested by the prevalence of the disease in Icelandic families. The Decode team, along with investigators from Reykjavik's National University Hospital, studied 772 living and deceased Parkinson's patients in Iceland over the past 50 years. They compared these patients with a national genetic database on 611,000 Icelanders who lived during the past 11 centuries.

The analysis showed that siblings of Parkinson's patients had a more than six-fold increase in their risk of the disease, regardless of the age of onset. The risk was tripled among children of Parkinson's patients, and more than doubled among nieces and nephews.

What remains unclear from both the Duke and Decode research is the extent to which conclusions based on these specific case studies can be extrapolated to the general population. It may be too early to know.

In the Iceland study, for example, "they may have found a predisposing factor that is rather specific for the Icelandic population, and may not be more generally applicable," Nussbaum suggests. Moreover, "such predisposing factors make notoriously poor diagnostic tests—because not everyone carrying the variant will develop the disease."

Still, says Kari Stefansson, chief executive officer of Decode, "many scientists and funding agencies had recently concluded that there was no identifiable genetic component to late-onset Parkinson's. We are very pleased to be able to counter this skepticism."

The genes vs. environment debate has benefited research.

J. William Langston, chief scientific officer of The Parkinson's Institute in Sunnyvale, California, who conducted studies of twins that suggested environmental factors as the primary cause of Parkinson's, urges caution in jumping on the genetics bandwagon. One study, published in 1999, looked at nearly 20,000 twins, both identical and fraternal, who were part of the WWII veteran twins registry maintained by the US National Academy of Sciences. They surmised that identical twins, who have the same genetic makeup, would both be expected to develop Parkinson's if genes were the cause. However, the disease occurred more often in just one member of a pair, whether identical or fraternal.

The Parkinson's Institute, a not-for-profit organization that specializes in neurological movement disorders, has also been looking at pesticides and other toxins as environmental factors, but there are no conclusive data as yet.

"In a sense, you've got a better chance of finding a gene than something in the environment, because you've got a finite number of genes, and the environment is endless," Langston says. "But people believe genes and genomics will solve anything—and that's not going to be the case."

The idea that something in the environment caused Parkinson's first arose in the 1920s, following a pandemic of encephalitis—Von Economo's encephalitis, which was caused by a viral agent that often resulted in a syndrome very similar to Parkinson's. Many survived the illness, but went on to develop what many physicians believed to be Parkinson's disease.

In 1982, students in California developed severe Parkinson's-like symptoms almost overnight after taking a synthetic heroin drug with a contaminant, a chemical known as MPTP. The drug had permanently damaged cells in the substantia nigra of the brain—damage like that seen in Parkinson's patients.

For many years, scientists in the field held to the theory that environmental exposure to one or more chemicals—pesticides, perhaps—was the culprit, combined with aging and some minor genetic component. Paradoxically, the environment-vs.-genetics debate has not really seemed to hurt either camp. In fact, the opposite may be true.

Langston recently received funding to go back to look at the roughly 150 sets of twins he previously studied to see whether the unaffected siblings have or are likely to develop the disease. His team will perform SPECT brain scans on the previously unaffected twins—a new technology to image dopaminergic terminals in the brain—to pick up preclinical evidence of Parkinson's while the individuals are still asymptomatic.

Perhaps the most interesting, and promising, aspect of current Parkinson's research is an increasing awareness of the complexity of the problem, including the likelihood that as more is learned, the interactions among genes and environmental factors will become clearer.

See related GNN articles
»Gene candidate mapped for late-onset Parkinson's disease
»Toxic triggers: genes, pesticides, and Parkinson's disease

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Martin, E.R. et al. Association of single-nucleotide polymorphisms of the tau gene with late-onset Parkinson disease. JAMA 286, 2245-2250 (November 14, 2001).
Scott, W.K. et al. Complete genomic screen in Parkinson disease: evidence for multiple genes. JAMA 286, 2239-2244 (November 14, 2001).
deCODE locates first gene linked to late-onset Parkinson's disease. Press release, deCODE Genetics, Reykjavik, Iceland (October 23, 2001).
Sveinbjörnsdóttir, S. et al. Familial aggregation of Parkinson's disease in Iceland. N Engl J Med 343, 1765-1770 (December 14, 2000).
Tanner, C. M. et al. Parkinson disease in twins: an etiologic study. JAMA 281,341-346 (January 27, 1999).

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