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Fly Model of Parkinson's Offers Hope of Simpler, Faster Research

By Michael Vatalaro

The solution to Parkinson's disease may lie in the brain of a fruit fly. Two NIH-funded researchers announced in March that they had created a strain of transgenic fruit flies that exhibit the signs and symptoms of Parkinson's disease. The new fly model of the disease holds the promise of simpler and more rapid research into a disabling disease that affects half a million Americans.

Dr. Mel Feany and Dr. Welcome Bender, who work at Harvard Medical School with support from the National Institute of General Medical Sciences and the National Institute on Aging, developed a strain of flies that produce the human protein alpha-synuclein. Synuclein has been associated with Parkinson's disease and causes damage to nerve cells in mice. When synuclein is expressed in the fly brain, structures appear there that are very similar to Lewy bodies, the dense, fibrous clumps of protein that are a pathological hallmark of Parkinson's disease.

"[The fly model] turns out to be surprisingly similar to the human disease," said Feany. The flies also display other symptoms of Parkin-son's, including the progressive loss of dopamine neurons and difficulty climbing, which is reminiscent of the loss of motor control in humans with the disease.

Parkinson's disease is a chronic, neurodegenerative disorder marked by tremors in the limbs, a characteristic gait, stiffness and difficulty controlling movements. Parkinson's typically appears in 50 to 60-year-olds, with around 50,000 new cases being diagnosed in the United States each year. Although several drugs help treat the symptoms, there is no cure.

The symptoms of the disease are caused by the death of dopamine nerve cells in a region of the brain known as the substantia nigra. It is estimated that 60 to 80 percent of the dopamine nerve cells in the substantia nigra have already died before symptoms begin to occur. The cause of the nerve cell death is unknown, but synuclein is a leading suspect.

Synuclein has been the subject of Parkinson's research since geneticists studying a group of people with a rare, inherited form of the illness discovered mutations in the synuclein gene. Synuclein is present in healthy brains, but it is also the major component of Lewy bodies. It is unclear whether the Lewy bodies are defensive, a sort of cellular hazardous waste barrel that the body uses to contain synuclein, or if they are part of the disease process and will ultimately be responsible for the death of the neuron.

The distinction is important and previously could not be tested. Now with the news of a fly model and a new mouse model of Parkinson's, both published within weeks of one another, researchers can begin to design experiments to answer that question.

However, the fly model offers distinct advantages over the mouse model. First, the Lewy bodies in the flies' brains contain thin fibrils of aggregated proteins, just like those in humans. The Lewy bodies in mice lack these filaments, which may affect how the Lewy bodies function within the cell. Second, the dopamine neurons in the fly brain die, as they do in humans, while in the mouse model they are only damaged. Finally, fruit flies are just more convenient to work with. They have a much shorter life span than mice — on the order of 2 months rather than 2 years — and are less expensive to raise and maintain.

The simplicity of the fly model also gives it the potential to be used in a variety of ways.

"The fly model is a more convenient way to screen for drugs than any mammal," said Bender. Feany and Dr. Peter Lansbury, an associate professor of neurology at Harvard whose work in this area is funded by the National Institute of Neurological Disorders and Stroke, are collaborating to begin rapid drug screening using the fly model. The fly model is ideal for testing new pharmaceutical compounds because thousands of flies can be raised and tested in a short time and in a limited amount of space.

In addition to providing an inexpensive way to test new drugs to combat Parkinson's, the fly model can be used by researchers to examine more carefully the formation of Lewy bodies and synuclein's role in that process. Feany also plans to continue to probe into the genetics behind the production of synuclein by studying the flies to look for proteins that enhance or suppress the toxicity of synuclein. Such studies could help determine whether Lewy bodies are benevolent or not.

Feany and Lansbury, a chemist who studies the structures of proteins and how they aggregate, are interested in studying Lewy body formation. There are some indications that the damage to the neurons occurs before or during, rather than after, the formation of the Lewy bodies.

But if fully formed Lewy bodies are indeed harmful, then finding the mechanism by which they form is critical. Once the mechanism is understood, it may provide drug makers with a target for developing new therapies aimed at preventing Parkinson's.

Until then, the fly model will provide some of the best means to continue basic research, concludes Feany. "We know so little about Parkinson's — we know so little about why [the neurons] die. We are excited about the fly system because we hope it will provide many new facets for other researchers to explore."

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