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.
Golbe, MD, professor of neurology, UMDNJ-Robert Wood Johnson
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
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
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,"
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