Body of evidence. Lewy bodies (stained tan, in center) are characteristic of Parkinson's disease.

Faulty Gene Behind Parkinson's?

Scientists have pinpointed the gene that, when defective, causes a hereditary form of Parkinson's disease in a large Italian family. The gene, described in tomorrow's issue of Science,* will probably account for only a few percent of all cases of the neurodegenerative disease, which has symptoms that include tremors and halting movements. But if researchers can pin down how the mutated protein exerts its effects, they may learn just what kills off crucial neurons in the much larger number of patients with nonhereditary Parkinson's.

For many years, most evidence suggested that an environmental factor, not heredity, is responsible for Parkinson's, in which a set of brain neurons that make the neurotransmitter dopamine gradually die off. Last November, however, a team led by Mihael Polymeropoulos of the National Human Genome Research Institute in Bethesda, Maryland, reported that the disease afflicting the Italian family, which develops at an unusually early age, showed strong genetic linkage to a region on chromosome 4.

By analyzing blood samples from more family members, Polymeropoulos's team was able to locate additional chromosomal markers that seemed to be inherited along with the disease. These markers allowed the group to narrow the suspect region of the chromosome to a 6-million-base-pair stretch of DNA that turned out to contain a promising gene: the alpha-synuclein gene. "All along, we knew that synuclein was a good candidate," says Polymeropoulos, because other researchers had shown that the protein is expressed in several brain areas, including the ones that deteriorate in Parkinson's.

Sure enough, when the researchers sequenced the gene in the Italian family, they found that the affected members had a mutation not present in unaffected members. The group found the same mutation in three of five Greek families with strong histories of the disease. But it did not appear in any of the more than 300 controls from France and Italy or in 52 Italian patients with sporadic Parkinson's disease.

Other researchers hail the finding. "It is a marvelous piece of work--of great importance," says C. Warren Olanow, a neurologist at Mount Sinai School of Medicine in New York City. "This is a major clue as to what might be going on." Demetrius Maraganore, a neurologist at the Mayo Clinic in Rochester, Minnesota, agrees: "It's the first major breakthrough in the understanding of the disease in 30 years."

Ultimately, a better understanding of what causes the neurodegeneration of Parkinson's may lead to better therapies for the condition. Although current treatments with drugs that replace the missing dopamine stave off the symptoms for a time, they lose their effectiveness as the patients' brains deteriorate. But learning what causes that deterioration might make it possible to design more specific drugs to prevent it.

* For more details, Science Online subscribers can link to the full text of the Report.