Gene Linked to 1 Type of Parkinson’s

Federal researchers have discovered the gene that causes an early-onset form of Parkinson’s disease that runs in families, a finding that should provide the first real insight into how the disease develops biochemically.

That understanding, in turn, may eventually lead to new treatments for--and perhaps even to ways to delay or prevent the onset of--the devastating disorder, which affects more than 1 million Americans.

A team from the National Human Genome Research Institute in Bethesda, Md., reports today in the journal Science that the defective gene that causes Parkinson’s produces a defective protein that may clump together to kill brain cells.

“This finding could prove to be the most significant advance in our understanding of Parkinson’s disease since . . . the mid-1960s,” said Dr. Harold Varmus, director of the National Institutes of Health. “It’s going to have implications not only for Parkinson’s, but for the study of cell biology in general and for understanding how a nerve cell works and how other diseases work.”

“I think this is going to be of major import,” said Dr. Abraham Lieberman of the Barrow Neurological Institute, medical director of the National Parkinson’s Foundation. “We now have the means of creating an animal model that truly mimics Parkinson’s. We then can do manipulations to see how it translates into a lethal disorder and what you can do to prevent it. We also can test drugs to slow the progression.”

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Intriguingly, fragments of the protein, called alpha-synuclein, are also present in the plaques and tangles characteristic of the other major neurodegenerative disorder, Alzheimer’s disease. This suggests that the newly recognized protein may play a role in its onset as well.

Researchers estimate that the newly discovered gene plays a role in most of the 10% to 20% of Parkinson’s cases that have a hereditary component, and some speculate that it is important in many of those cases not associated with a family history of the disease.

By some projections, the number of afflicted Americans could increase to about 4 million by the year 2040. Parkinson’s disease strikes about 60,000 people in the United States each year.

The disease is characterized by tremors and rigidity in the limbs, slowness of movements and loss of muscle control, all of which worsen with age. As many as a third of patients also develop dementia, an impairment of thought processes.

Symptoms are caused by the death of brain cells that secrete a chemical called dopamine, which plays a key role in the transmission of commands from the brain to muscles. The disease is treated primarily with drugs or fetal cell transplants that boost dopamine levels in the brain.

Discovery of the gene will, for the first time, make it possible to identify at least some people who are at high risk of developing the disease, making it possible to begin treatment as soon as symptoms appear. Growing evidence suggests that treatment early in the course of the disease can slow progression, according to Dr. C. Warren Olanow of the Mt. Sinai School of Medicine in New York City.

The research team, headed by geneticist Mihael Polymeropoulus of the genome institute, studied DNA from 28 members of an extended Italian family containing almost 600 people, more than 60 of whom have been diagnosed with Parkinson’s. The family traces its ancestry to a single Parkinson’s patient who lived in Contursi, a small Italian village near Salerno, in the 18th century. Members develop the disease at an average age of 46, about 10 to 15 years earlier than victims of the sporadic, non-inherited form.

Last November, the genome institute team announced it had localized the search to a narrow region of Chromosome 4, one of the 23 pairs of chromosomes that make up the human genetic blueprint. But that region contained at least 100 separate genes and scientists were unsure how long it would take to find the right one.

One of those genes, however, was for alpha-synuclein, which was known to play a role in the brain. “All along, we knew that synuclein was a good candidate,” Polymeropoulus said, because other researchers had shown that it was produced in the areas of the brain affected by Parkinson’s.

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When they sequenced the gene--determining the identity of each of the 450 chemicals that compose it--they found a mutation at one site in the gene in each family member who had Parkinson’s. That mutation was not present in family members who did not have the disease, nor was it found in 100 healthy people from southern Italy.

Subsequent studies showed that the same mutation was present in Parkinson’s patients from three of five Greek families with a strong history of the disease, confirming its importance. The researchers did not find the mutation, however, in 52 Italian patients with sporadic Parkinson’s.

Polymeropoulus noted that these other Parkinson’s patients could have a different mutation in the alpha-synuclein gene. Moreover, he noted, “there is evidence that there are similar genes hiding elsewhere in the genome. One of our first tasks is to track them down.”

The team does not yet know what role healthy alpha-synuclein normally plays in the brain or how the defect can trigger disease. But they suspect that the mutation leads to an abnormal protein structure that might cause individual alpha-synuclein molecules to aggregate into destructive clumps.

Polymeropoulus speculated that pharmaceutical companies might soon begin looking for drugs that would prevent such aggregation. A similar search is already being conducted with Alzheimer’s disease, in which proteins called beta-amyloid aggregate in a similar fashion.

Such treatment could be begun once symptoms appear, but eventually it might be used to prevent symptom occurrence in people with the gene.

“For the first time since the disease was discovered in 1817,” Polymeropoulus concluded, “[we have] the ability to begin developing drugs aimed at the cause of the illness rather than the symptoms.”

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Parkinson’s Discovery

Researchers have discovered the gene that causes an early-onset form of Parkinson’s disease that is inherited. The gene serves as the blueprint for a protein called alpha-synuclein.

* Researchers are not sure what alpha-synuclein normally does in cells, but it is found at the synapses, the space between neurons.

* Mutated alpha-synuclein has an abnormal shape that causes it to aggregate into clumps that kill cells, researchers believe.