Genetic Link to Parkinson's Is Discovered

By Rick Weiss
Washington Post Staff Writer
Thursday, January 26, 2006

Researchers said yesterday that they have identified a single genetic mutation that accounts for more than 20 percent of all cases of Parkinson's disease in Arabs, North Africans and Jews, a big surprise for a major disease in which genetics was thought to play a relatively minor role.

Although the mutation is rare in people with ethnic roots outside the Middle East, its discovery raises the prospect that undiscovered mutations may be major causes of Parkinson's in other groups.

"Genetics are going to be a lot more important in Parkinson's than people have appreciated," said study leader Susan Bressman, a neurologist at Albert Einstein College of Medicine of Yeshiva University and Beth Israel Medical Center in New York.

The finding -- described in a pair of reports in today's New England Journal of Medicine -- could help reveal at last the mysterious underpinnings of Parkinson's, which causes tremors, rigidity and mental decline and is growing more common as the population ages.

But it also raises the delicate question of whether some people should be offered tests to see if they harbor the predisposing glitch -- a tough call, as there is no known way to prevent the disease.

In this era of Arab-Israeli tensions, the discovery of shared genetic flaws might even serve as a small olive branch, scientists said.

"Yasser Arafat once said we are all cousins. Well, it's the truth," said Neil Risch, director of the University of California at San Francisco's Center for Human Genetics.

Parkinson's affects at least 500,000 Americans and has no cure, though drugs can slow its progression. Studies have long hinted that most cases arise from a combination of environmental factors -- almost none of which have been identified, though some studies have implicated pesticides -- and many small mutations, presumed to be of little effect individually.

The new work focuses on a gene called LRRK2 (for leucine-rich repeat kinase 2), which carries the instructions that brain cells need to make a protein called dardarin.

The gene has been under scrutiny since 2004, when a rare mutation within it was linked to Parkinson's in a handful of families in the Basque region of Spain and France. "Dardarin" is a form of the Basque word for "tremor."

In the new work, researchers studied a different mutation in the same gene.

Like all proteins, dardarin is a string of amino acids -- 2,527 of them in all. In people with the newly studied mutation, cells make an abnormal version of dardarin in which amino acid No. 2,019 is glycine instead of serine.

That tiny change -- which Risch thinks occurred by chance in a single person in the Middle East perhaps 2,000 years ago -- can lead to a big difference in people's brains.

In one of the two new reports, led by Bressman and Laurie J. Ozelius of Albert Einstein College, researchers tested the DNA of 120 Ashkenazi Jews with Parkinson's and 317 healthy Jews. Ashkenazis are Jews of recent Eastern European descent who represent the vast majority of Jews worldwide.

More than 18 percent of the patients harbored the glycine-to-serine error, while only about 1 percent of healthy Jews had it. About a third of those with the mutation can expect to get Parkinson's, meaning the error increases one's risk 15- to 20-fold.

The second study, led by Suzanne Lesage and Alexis Brice of INSERM, a research institute in Paris, looked for the same mutation in 104 Arabs and North Africans with Parkinson's and in 151 healthy Arabs. About 40 percent of patients had the glitch, compared with 3 percent of controls.

All told, the team said, the mutation may account for 30 percent or more of Parkinson's cases in this population. Jews and Arabs are not known to have high rates of Parkinson's, hinting that other mutations may be key in other ethnic groups.

In fact, other mutations in the LRRK2 gene show hints of being linked to Parkinson's in other ethnic groups, making the gene an exciting target for scientists longing to know what is at the root of the disease. And unlike the few other genes that have been linked to increased rates of Parkinson's, most of which cause atypical versions of the disease, LLRK2 mutations cause standard-issue Parkinson's.

The precise role of dardarin in the brain is uncertain, but its main job seems to be to attach chemical groups called phosphates to other proteins -- a decoration that can help proteins coordinate their activities inside cells. Lab tests show that mutated dardarin can become overactive, showering extra phosphates on proteins and potentially garbling their interactions.

Together with recent revelations that some proteins in the brains of Parkinson's patients seem overly endowed with phosphates, these findings hint that drugs designed to temper that biochemical process might prevent the disease or slow its progress.

Experts differed on the wisdom of offering LRRK2 gene tests to people of Middle Eastern ancestry.

Bressman favors it, though only in the context of good counseling in advance. Others disagreed.

"Before we put tests into clinical practice, we have to have something to tell the patient who is asking, 'Now what do I do?' " said Ephrat Levy-Lahad, director of medical genetics at Shaare Zedek Medical Center in Jerusalem.

But testing could be a boon for research, said Mary-Claire King, a University of Washington geneticist studying genes linked to breast cancer in Ashkenazi women.

Until now, efforts to identify other genes or environmental factors that might influence one's odds of getting Parkinson's have been hampered by the fact that most people, exposed or not, do not develop the disease. By studying people with LRRK2 mutations and finding commonalities among those who do or do not get Parkinson's, the search for contributing factors could take off, King said.

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