Finding a Genetic Connection T he way forward was to work with families and to do DNA analysis. And that is precisely what Dr. Duvoisin and his team did. Dr. Lazzarini published a family study from the medical files of hundreds of Dr. Duvoisin’s patients. A significant opportunity presented itself when Dr. Golbe had serendipitous encounters with two Parkinson’s patients whose families included multiple members with the disease. Both families came from a small village in southern Italy, Contursi, in the province of Salerno. The hunt for answers was on. Dr. Golbe recruited a collaborator, Giuseppe Di Iorio, MD, a neurologist at the nearby University of Naples. Together, they found that 61 of the town’s descendants had developed Parkinson’s disease. They traced the ancestry of all 61 to a couple who had lived in the late 1600s. This rare family demonstrated a classic single-gene inheritance pattern. Men and women were equally affected, children of affected persons had a 50 percent chance of carrying the mutated gene, and almost every person with the gene developed the disease. Known as the Contursi Kindred study, it provided enough data—through this one extended family—to use to find a causative gene. The next step was to locate and identify that gene. Both Dr. Golbe and Dr. Lazzarini made trips to Contursi to collect blood samples for DNA analysis back in New Jersey. Dr. Duvoisin’s team had already confirmed—through examinations of autopsy materials from two deceased family members— that this atypical family did demonstrate typical Parkinson’s pathology. This was the first demonstration of typical Parkinson’s autopsy pathology in patients with hereditary Parkinson’s. “Earlier in his career, Dr. Duvoisin was known to advocate for environmental causes of the disease. Then, once evidence demonstrated otherwise, he announced publicly that he had changed his mind and now believed it was genetic. That had a really big influence on the whole field,” says Dr. Golbe. “Very few people agreed with him.” The Protein Discovery D r. Duvoisin and his group formed a collaboration with the NIH’s Robert Nussbaum, MD—a clinical geneticist with advanced training in molecular biology—and his colleague Mihaelis Polymeropoulos, MD. They found the locus of the gene mutation on chromosome 4—at the address 4q21. Checking for genes located in the same area against GenBank—the repository of millions of gene sequences—they found a candidate gene that had been described by two California scientists. The gene was called SNCA, which coded for a protein called alpha-synuclein. In June 1997, Dr. Nussbaum, Dr. Polymeropoulos, and Dr. Duvoisin’s team submitted their paper, “Mutation in the Alpha-Syneuclein Gene Identified in Families with Parkinson’s Disease,” to the journal Science. In it, they identified the first of many mutations, in the alpha-synuclein gene, that cause Parkinson’s disease. Soon after the findings were published, other scientists searched for abnormal alpha-syneuclein in brain tissue from people with nonfamilial Parkinson’s disease. They showed that it’s the main component of the protein aggregates called Lewy bodies, which create a toxic effect inside the brain cells of people with Parkinson’s. Since then, other mutations in the same gene, SNCA, have been found to increase the risk of Parkinson’s even in its more common nonfamilial form. “Our discovery changed the face of Parkinson’s research forever,” says Dr. Lazzarini. “It is considered to be the single most promising scientific opportunity in the search for the cure for Parkinson’s disease.” Now approaching 90 years of age, Roger Duvoisin lives in North Carolina. He and Dr. Lazzarini—who, in the ultimate twist of fate, has been diagnosed with Parkinson’s disease herself—still keep in touch. “He wants us to write a book to commemorate the anniversary of James Parkinson’s 1817 description of ‘the Shaking Palsy,’” she says. The American Parkinson Disease Association has named a research scholar award for Dr. Duvoisin. Today, the search continues for ways to apply his team’s discovery to neuroprotective therapies, and early clinical trials have begun that engage in various approaches to target alphasynuclein, including the use of antibodies. Unquestionably, the role that Dr. Duvoisin played in the discovery of alpha-synuclein has hastened the promise of a successful treatment for this devastating disorder. M Robert Wood Johnson I MEDICINE 21