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Exploring Parkinson's disease, with a little help from flies
By Bijal P. Trivedi

By placing a human gene linked to Parkinsonís disease into Drosophila, researchers have caused flies to develop some symptoms of Parkinsonís. The flies develop the same degeneration of neurons, abnormal cell characteristics, and movement and coordination problems seen in human patients. The work is reported in the March 23 issue of Nature.

The brains of Parkinsonís patients are characterized by abnormal clumps of cells called Lewy bodies, which are rich in the protein alpha-synuclein. But whether Lewy bodies actually cause Parkinsonís disease is unknown. "Thatís why we need a model system," says Mel Feany, of Brigham and Womenís Hospital and Harvard Medical School in Boston. "All we know at this point is there is an association between the two. Using flies, we can ask whether Lewy bodies cause the disease or modify it somehow."

Feany and co-author Welcome Bender are also collaborating with Peter Lansbury, of the Center for Neurologic Diseases at Brigham and Women's Hospital, to study the effects of candidate drugs on neuron degeneration and Lewy bodies in the flies carrying a copy of the human alpha-synuclein gene.

Feany and Bender bred three types of flies with the human alpha-synuclein gene. The first type of fly had a healthy copy of the gene, and the two others were bred with mutated versions of the gene that are found in some patients with inherited Parkinsonís disease.

All flies with the normal or mutated alpha-synuclein gene had Lewy bodies and degenerated dopaminergic neurons. These flies also developed movement difficulties at an age of between 20 and 30 days—middle age for a fly. Normal flies of the same age showed none of these characteristics. When nerve cells in the substantia nigra, the area of the brain that controls the fluidity of movement, send signals to other parts of the brain, they use dopamine to transmit the messsage.

Cross section of a healthy human brain stem. Neurons that communicate using dopamine appear as a dark band.

In Parkinsonís patients, neurons using dopamine are lost.

The researchers tested the fliesí motor skills by placing them in a glass jar and watching them climb to the top, something normal flies can do rapidly. Twenty-day-old flies with the normal or mutant alpha-synuclein gene were unable to reach more than half way up the glass walls before falling down. As the flies aged, theyíre climbing ability deteriorated. But alpha-synuclein may not be the sole cause of the disease.

Humans have differing susceptibilities to Parkinsonís, which suggests that there are other "modifier genes" playing a role in the disease, says Feany.

In current and future experiments Feany is looking for genes that either prevent or decrease the loss of nerve cells and formation of Lewy bodies. Heís also looking for genes that make these symptoms worse. "We want to find completely novel genes associated with Parkinsonís. Any gene that alters the symptoms in flies—make the neurodegeneration or locomotion problems worse, or delays the onset of disease—is a good candidate for a role in people," he says.

If a gene is able modify the Parkinsonís-like disease in flies, the researchers hope that the equivalent gene in humans would do the same thing.

Already Feany has some genes that suppress the onset of the disease by about 10 days and others that prevent the formation of Lewy bodies. But whether these genes can stop the disease remains to be seen.

See related GNN article
»The Humanized Fly

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Feany, M.B., Bender & W.W. A Drosophila model of Parkinson's disease. Nature 404, 394-398 (March 23, 2000).

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