Mar. 24, 2000 Model Could Speed Search for New Therapies
BOSTON (March 23, 2000) -- Flies harboring versions of a human gene could help solve a central mystery concerning Parkinson's disease, a neurodegenerative disorder that currently affects more than a half a million Americans.
For several years, researchers have observed dense dots of protein, each surrounded by a halo-like ring, inside neurons deep within the brains of people with Parkinson's disease. But their true nature has been confusing. Are they killing neurons, thereby bringing about the motor deficits--shakes, tremors, and rigidity--that characterize Parkinson's? Or are these haloed intruders actually do-gooders, protecting the cell from other poisonous proteins?
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, MD, PhD, Instructor in Pathology, Brigham and Women's Hospital and Harvard Medical School, and Welcome Bender, PhD, Professor, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, report that they have created the first fly model of Parkinson's disease--one that replicates not just the dense Parkinson inclusions, called Lewy bodies, but also symptoms of the disease, including motor deficits such as an inability to climb. They did this by expressing a 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 disease can be tested--and tested quickly. The short life span of the flies also make them ideal for testing new drugs and other therapeutic approaches.
Alpha synuclein was first discovered in human Lewy bodies three years ago. Since then researchers have been racing to express the protein in non-humans in the hope of creating animal replicas of Parkinson's. Last month, a team of researchers reported that they had expressed the normal alpha synuclein gene in mice. The animals exhibited dense neuronal inclusions resembling Lewy bodies in the substantia nigra, as well as locomotor abnormalities.
It appears the flies replicate even more faithfully the pathology of the disease. For example, human Lewy bodies are studded with stringy bits of protein, or fibrils--a feature found in the flies but not in the mice. Also, people with Parkinson's disease experience a loss of dopamine-producing neurons in a particular brain area, the substantia nigra. 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 replicas. But the relative genetic simplicity of the fly model may be its greatest advantage, says Feany. 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 disease. 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 enemy. "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 could get thicker. 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," says Feany.
Feany and Bender 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 brains of the flies with the mutant gene--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 this ability 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, the Lewy bodies of flies with a mutant version of the alpha synuclein gene appeared, under electron microscopy, to be fibrillar--as they are in humans.
The flies may have a near-term pay-off 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, to find small molecules that either enhance or inhibit Lewy body formation in vitro and she plans to test those molecules in her fly model.
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