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PATHOLOGY First Fly Model of Parkinson's ReportedCould Speed Search for New Drugs Against the Disease Flies harboring versions of a human gene could help solve a central mystery of Parkinson's disease, a neurodegenerative disorder that affects more than half a million Americans. For several years, researchers have observed dense dots of protein, each surrounded by a halolike ring, inside neurons deep within the brains of people with Parkinson's. But the true nature of the clumps has been confusing. Are they killing neurons, thereby bringing about the motor deficits—shakes, tremors, and rigidity—that characterize the disease? Or are these haloed intruders actually do-gooders, protecting the cell from other poisonous proteins?
Mel Feany and Welcome Bender (l to r) have engineered flies that reproduce the symptoms of Parkinson's disease. Until recently, researchers have been stymied in their quest to answer these and other questions about Parkinson's disease by the lack of a good animal model. In the March 23 Nature, Mel Feany and Welcome Bender report that they have created the first fly model of Parkinson's—one that replicates not just the dense Parkinson inclusions, called Lewy bodies, but also the motor deficits such as an inability to climb. They did this by expressing a human protein, alpha synuclein, in the flies' brains. What makes the mutant flies especially powerful as a model, in addition to their replication of the pathology and symptoms of Parkinson's disease, is their short life span. Ideas about the role of Lewy bodies in Parkinson's can be tested—and tested quickly. The short life of the flies also makes them ideal for testing new drugs and other therapeutic approaches. New Protein on the BlockAlpha synuclein was first discovered in human Lewy bodies three years ago. Since then researchers have been racing to express the protein in nonhumans in the hope of creating animal replicas of Parkinson's disease. Last month, a team of researchers reported that they had expressed the normal alpha synuclein gene in mice. The animals exhibited locomotor abnormalities and dense neuronal inclusions resembling Lewy bodies in a particular area of the brain, the substantia nigra. This is the area where people with Parkinson's experience a loss of dopamine-producing neurons.Yet it appears the flies replicate even more faithfully the range of pathologies associated with the disease. For example, human Lewy bodies are studded with stringy bits of protein, fibrils, a feature found in the flies but not in the mice. The flies exhibited a loss of dopaminergic neurons whereas the mice showed only a decrease in the terminals, or ends, of the neurons. Actual death of dopaminergic neurons was not documented in the mice. Of course, the mice are closer to humans from an evolutionary and genetic point of view and, in this sense, may be better models. But the relative genetic simplicity of the fly may be its greatest advantage, says Feany, who is an instructor in pathology at Brigham and Women's Hospital and HMS. Now that the entire fly genome has been sequenced, pursuing genetic partners of alpha synuclein is markedly easier. Feany plans to use the flies to see what other genes are involved in Parkinson's. By suppressing or enhancing those genes, along with alpha synuclein, she hopes to see how exactly Lewy bodies are formed. With such knowledge, she may be in a position to figure out the Lewy bodies' true nature—friend or foe. "We can look at the effect of inhibiting Lewy body formation on loss of dopaminergic neurons, a hallmark of Parkinson's disease," she says. If more neurons live, then Lewy bodies are bad. If more die, then they may be serving a protective function. But the plot may thicken. For example, there is evidence that Lewy bodies may be mopping up a toxic protein—and that protein could be alpha synuclein. "Lewy bodies may be the best thing that ever happened to the Parkinson brain because they're actually sopping up a lot of evil synuclein," Feany says. Modeling the DiseaseThat's a heavy role for a protein that until very recently was believed to have nothing to do with Parkinson's. In fact, it was only three years ago that several affected members of an Italian family were found to have mutated versions of the alpha synuclein gene. Though most people with Parkinson's do not have mutant versions, the alpha synuclein protein was soon shown to be present in the Lewy bodies of Parkinson's patients, suggesting it played a role in the disease.
The eyes have it. One of the advantages of the new Parkinson's flies is that they can be detected at a glance because Mel Feany expressed human alpha synuclein in the eyes of the flies. Normally, the array of photoreceptors found in fly eyes produces a characteristic pattern, called the pseudopupil (left). Flies carrying the alpha synuclein gene have a discernibly abnormal pseudopupil (right).I mages courtesy of Mel Feany To clarify the role, Feany and Bender, who is the Harold T. White professor of biological chemistry and molecular pharmacology at HMS, introduced both normal and mutant versions of the human alpha synuclein gene into flies and then looked for signs of Parkinson's. One of the first things they observed was loss of dopaminergic neurons in the fly brains—but only in the adults, not the young. "The key was to show that these changes were degenerative rather than developmental," Feany says. Similarly, the motor defects appeared only in the adults. Normally, when flies are tapped to the bottom of a vial, they climb to the top, where they remain. Although normal flies lose this ability as they grow old, the mutants lost it at a much earlier age. Perhaps most compelling of all were the Lewy bodies exhibited by the mutants. Not only were they visible by light microscopy, they appeared under electron microscopy to be fibrillar as they are in humans. "We were very pleased about that," Feany says. Flying to the RescueFiguring out whether the Lewy bodies are playing a pathogenic or protective role is Feany's next goal—and the answer will be of vital importance clinically. Depending on what she finds, one would either want to inhibit or enhance Lewy body formation to fight disease. One step toward that end would be to find out which proteins normally suppress or enhance their formation in the flies. "It's this long-term potential to identify new molecular targets that would excite drug companies," she says.But the flies may have a more immediate payoff as drug screens. Because flies reproduce very quickly, it is possible to throw all kinds of potentially therapeutic molecules at them and see which ones make a difference. Feany is currently working with Peter Lansbury, associate professor of neurology at BWH, to find small molecules that either enhance or inhibit Lewy body formation in vitro, and she plans to test these molecules in her fly model. "What's most exciting about the model is that new molecules involved in Parkinson's disease will be discovered through genetics. We make no assumptions about what we might find," she says. Bender agrees: "The lure of genetics is that you can discover things that you hadn't imagined." —Misia Landau |
