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Gene Hunter
by Eve Jacobs

The culture, the cuisine, the natural beauty, the art treasures of sunny Italy attract hordes of visitors yearly. But few journey there to knock on the doors of strangers in an outlying village, beseeching them - through a translator - to donate some of their DNA to aid in the hunt for disease-causing genes. Larry Golbe has done that.

Lawrence Golbe, MD, professor of neurology, UMDNJ-Robert Wood Johnson Medical School.

This neurologist's life was radically changed by a meeting. Nearing completion of his neurology residency at New York's Bellevue Hospital, he was headed into practice until an hour spent with world-renowned Parkinson's disease (PD) expert Roger Duvoisin spun him around and landed him in a different spot. Invited by the then-chair of UMDNJ-Robert Wood Johnson Medical School's neurology department to join his research and clinical team, Golbe spotted a golden opportunity and took it.

The year was 1982, and the encounter proved pivotal for both doctors. It also proved critical to the unfolding tale of a disease that affects the mobility and well-being of half a million people in the U.S. alone. With new chapters still being written two decades later, it's a story of how sound science, quick thinking and sheer determination can spark a sudden "breakthrough," this one described as "one of the most significant developments in the history of Parkinson's disease," by the National Institute of Neurological Disorders and Stroke.

The genetics of Parkinson's had been a keen interest of Duvoisin's for some time. He had studied its incidence in twins, and since 1980, had been examining patterns of inheritance in familial clusters of the disease. He was particularly careful to record accurate family histories from all of his patients, according to Golbe.

In 1986, Duvoisin referred some of his patients with difficult-to-manage Parkinson's symptoms into an experimental drug trial in his department. Golbe was directing the trial.

One patient did quite well on the experimental drug, according to Golbe, but suddenly died by drowning. The day after his funeral, the victim's brother contacted the neurologist and asked if he would take care of him. The brother also had Parkinson's.

At this point, Golbe decided to start an "extended horizontal search" into the family, looking for potential cases of Parkinson's. He found six affected members. "That's a lot for one family," he comments. He asked his patient where the family originally came from and was told Contursi, Italy. He recorded that piece of information along with the rest of the family's history.

"A few months later, I was talking with a woman in the drug study who did not have an Italian last name. I was leafing through her chart and saw that her family history, which Dr. Duvoisin had obtained years before, showed several relatives with Parkinson's. I asked where her family originated and she said Contursi, Italy," recalls the neurologist.

Bingo! Uncovering this critical connection set off bells in Golbe's brain. He contacted Giuseppe DiIorio at the University of Naples, a neurologist with a research interest in genetics, and asked him to be the Italian arm of their research team. The Italian neurologist signed on, even though the gene hunt would prove labor intensive and require many trips to Contursi, a village of 5,000, which is a six hour drive from Naples. The year was 1987.

While DiIorio managed the Italian front, Golbe traveled the U.S. - to track down members of this extended family. A few family members who had emigrated from Contursi to Argentina, Germany and northern Italy were contacted by other neurologists.

"We needed to locate as many members of this family as possible to increase the chances of finding the gene," he explains.

While most family members were very welcoming, DiIorio was once greeted with a shotgun at an Italian farmhouse and decided to do without that person's DNA sample. Golbe traveled to Contursi in 1995 to confirm and extend DiIorio's results.The research team discovered three separate families in Italy and three in the U.S. who shared a common ancestor but did not know one another. Golbe and DiIorio established the full genealogy of this family through 12 generations to an ancestral couple who lived in Contursi in the late 1600s and early 1700s.

This confirmed that the family disease is in fact Parkinson's; and showed for the first time that Parkinson's disease can be inherited. Of 400 identified family members to date, 61 have had it. (Golbe's first publication on this family, in 1990, included two autopsied cases.) The disorder is autosomal dominant and "fully penetrant," which means that each child of an affected person has a 50 percent chance of developing the disorder some time in his or her life. The average age at which PD begins in this extended family is only 47, significantly less than the average "garden variety" PD onset age of 60.

Through the early 1990s, RWJMS geneticists Alice Lazzarini and William Johnson worked with the DNA samples in an attempt to isolate the disease causing gene. They formed a collaboration with the Human Genome Project, part of the NIH, in 1995 to take advantage of their tremendous laboratory resources. In October 1996, the team announced that they had identified a small region containing approximately 100 genes on the short arm of chromosome 4 as the general site of a gene mutation that causes the disease in this family. The finding was reported in the journal Science and made headlines.

In June 1997, they discovered the specific gene mutation that causes Parkinson's in this family and reported it that month in Science. That paper showed that the mutation resided in the gene for alpha-synuclein, a protein known since 1988 to exist in the brain but not previously suspected of a connection with PD.

Within days of Golbe and his colleagues publishing their finding, researchers in several labs around the world tested the mysterious blobs of protein in the brain cells in PD for the presence of alpha-synuclein. They found that protein to be a major and fundamental component of those blobs, called "Lewy bodies." This demonstrates that even in the vast majority of patients with PD who harbor no genetic mutation in alpha-synuclein, the protein's malfunction is a fundamental step in the disease process. This discovery changed the direction of research into PD by providing scientists with an entirely new protein whose manufacture, function or breakdown could be the key to the disease.

Today Golbe continues his passionate unraveling of the genetics of the disease. He's particularly interested in the genetic factors governing the age of onset, which ranges from 22 to 86 in the Contursi kindred, and why the symptoms differ when the disease comes on early in life.

This year, his team discovered that a variant in the gene that codes for the enzyme glutathione-S-transferase (GST) affects the age of onset of Parkinson's in the Contursi kindred and also members of several Greek families with the same gene mutation causing Parkinson's. According to Golbe, the GST enzyme seems to detoxify one or more agents that speed up the loss of neurons in these individuals. "This is consistent with the theory that Parkinson's is at least partly the result of a toxin or toxins," he explains.

Golbe says the next step is to figure out what makes alpha-synuclein aggregate with itself in garden variety Parkinson's: "If we could identify it and then remove it, we could prevent the disease. That is quite within reach."

Insertion of an abnormal alpha-synuclein gene into mice, fruit flies and roundworms has made the study of PD and potential treatments for it easier than was possible with earlier animal models that did not mimic the alpha-synuclein abnormality that is fundamental to human PD. "These new animal models wouldn't have been possible without the Contursi kindred," Golbe says.

He is also working on the genetics of a lesser-known neurological disorder called progressive supranuclear palsy (PSP), which is superficially similar to PD, but causes more difficulty with behavior, eye movement, swallowing and balance. As in Parkinson's, a "protein gloms up in the brain," says Golbe. In the late '80s, the protein was discovered to be tau; and the first animal model of the disease that incorporates the abnormal tau was created in 2000.

Golbe has devised a clinical rating scale for PSP that is now in use all over the world. He also does epidemiological research focusing on dietary risk factors for the disease and chairs the scientific advisory board of the Society for Progressive Supranuclear Palsy.

In taking care of PD patients, Golbe says, "There are many drugs that can benefit patients, even at advanced stages of the disease. More neurologists need to learn to use them."

"And there is a lot of service we can render PSP patients," he continues. "The drugs so far are not really effective, but we can give an accurate diagnosis and prognosis; and help avoid complications such as choking on food and falling."

Golbe is currently on the steering committees of two epidemiological studies looking for siblings with Parkinson's. Both are fully supported by the NIH and "both are turning up genetic associations not previously suspected."

For his groundbreaking discoveries and his lifelong dedication to better understanding Parkinson's disease and progressive supranuclear palsy we recognize Larry Golbe as one of America's "top docs."