Scientists Make Headway In Parkinson's Research

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Scientists Make Headway In Parkinson's Research

February 18, 2000

Medical Tribune

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.

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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.