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Scientists Make Headway In Parkinson's Research
February 18, 2000

In a step forward in Parkinson's disease research, an international team of
scientists announced they have developed a strain of mice that displays
deficits in both the brain and in behavior that are characteristic of
Parkinson's disease.

Using an animal model of this degenerative brain disorder, researchers can
now better understand how Parkinson's causes the brain to malfunction and,
from that, learn how to prevent the disease from progressing or even
occurring at all.

Parkinson's disease is a neurological disorder that begins gradually and is
characterized mainly by tremors. Usually, these tremors begin in the hand,
but they can spread to the arms, legs and face. Parkinson's patients also
experience muscle stiffness and have difficulty initiating movements.

The typical Parkinson's patient is 65 or older, though the disease can start
earlier in life. As the disorder progresses, patients can experience extreme
difficulty with simple motor tasks, like walking or tying one's shoes.

In a study published in the February 18 issue of the journal Science
(www.sciencemag.org), the research team reported that they developed a
strain of mice that possesses the human gene that codes for a protein called
alpha-synuclein. Large deposits of this protein can be found in the brains
of Parkinson's patients, but scientists were uncertain if these deposits -
called Lewy bodies - were a cause or a result of the disease. They now have
good evidence that alpha-synuclein deposits help bring about the condition.

The researchers, headed by Dr. Eliezer Masliah, professor of neurosciences
and pathology at the University of California, San Diego, injected the human
gene for alpha-synuclein into fertilized mouse egg cells. They then
implanted these zygotes into female mice.

These mice gave birth to animals that had high levels of alpha-synuclein in
their brains. The scientists then used these animals to breed a whole strain
of mice that expresses the human gene for alpha-synuclein in their brains.

The researchers found that these genetically engineered mice had severe
deficits in motor skills, similar to the problems experienced by Parkinson's
patients.

Upon examining the brains of these animals, Masliah and his colleagues also
found accumulations of alpha-synuclein in the same areas - the neocortex,
hippocampus, olfactory bulb and substantia nigra - where Lewy bodies
typically form in Parkinson's patients. The mice also showed a reduced
number of brain-cell terminals in the basal ganglia that dealt with the
chemical signal dopamine.

Dopamine deficits in the basal ganglia are common in Parkinson's patients,
and drugs that block the effects of dopamine in the brain have been known to
cause Parkinson's-like symptoms.

"These results suggest that blocking the accumulation of alpha-synuclein
might help prevent or treat Parkinson's and related conditions," said Dr.
Lennart Mucke, coauthor on the study and professor of neurology and
neuroscience at the University of California, San Francisco.

The report was a collaboration among scientists at UCSD, UCSF and the
Yokohama City University in Japan.

Researchers at UCSD began working with the gene for alpha-synuclein in 1993.
They initially studied the gene's relationship to Alzheimer's disease.
(Alzheimer's and Parkinson's often overlap in older patients, and both
conditions appear to be caused by protein buildups in the brain.) However,
in 1997, data emerged indicating that alpha-synuclein was involved in
Parkinson's disease, and the researchers switched their focus.

Masliah said that in this animal model, the Parkinson's-like disease is
caused by an overexpression of the alpha-synuclein gene and not a mutation
in the gene.

"The idea is to use this model to develop compounds that will block the
aggregation of alpha-synuclein in an attempt to develop a new therapy for
Parkinson's disease," said Masliah. "Basically, we have already embarked on
that project."

He added that his research team will likely distribute these animals to
other interested academic scientists to speed along Parkinson's research.

"This is very significant. We haven't had a model like this before," said
Creighton Phelps, director of the Alzheimer's Disease Research Centers
Program at the National Institute on Aging (www.nih.gov/nia), in Bethesda,
Md.

"It's an animal model of part of the symptoms and part of the pathology [of
Parkinson's], but what it's showing is that alpha-synuclein has a key role,"
he continued. "So if you could find a way of blocking the effect of
accumulations of too much alpha-synuclein, then perhaps you could transfer
this information to treating people who might have the same problems."

Phelps added that, like Parkinson's patients, people with Alzheimer's often
develop Lewy bodies in their brains. "There's something in common that's
happening here. It will be interesting to see what effect stopping the
alpha-synuclein would have on other diseases," he said. "It might have a
broader context."

Science (2000;287:1265-1269)

Copyright 2000 Medical PressCorps News Service. All rights reserved.