What causes neurodegenerative diseases such as Parkinson’s and Alzheimer’s? How are such diseases best treated? For answers to these questions, researchers are probing the neurons of fruit flies and tiny worms called nematodes—and they are making some surprising and useful discoveries.
“Fruit flies have many strengths as animal models of disease,” says Mel Feany, an assistant professor of pathology at Harvard Medical School. The insects are cheap to raise and they mature and reproduce quickly. Their short life span makes studies of mutations, inheritance, and disease progression relatively quick and simple.
Fruit flies have many genes in common with higher animals, including humans. Researchers can easily transplant genes from humans into fruit flies. Finding mutations and observing the characteristics they produce are easier in fruit flies than in other types of animals.
Feany’s laboratory has bred a strain of the fruit fly Drosophila melanogaster that models Parkinson’s disease. Her team implanted mutant genes in the flies for a protein called alpha-synuclein.
Flies carrying the mutant genes lose dopamine-producing neurons in the brain’s substantia nigra, just as humans with Parkinson’s do. Also, fibrous bundles of alpha-synuclein form in the insects’ neurons. Bundles of the same structure and composition (called Lewy bodies) develop in the brain cells of people with Parkinson’s.
Cellular changes in the flies correlate with behavioral changes. Normal fruit flies climb up the sides of plastic vials. Middle-aged flies carrying the transplanted, mutant gene lose that ability.
“They can’t hang on to the sides and just fall to the bottom,” Feany explains. The loss of motor control in the flies mirrors the movement disorders observed in humans who have Parkinson’s.
Fruit flies are not the only simple organisms that have a lot to teach us about neurodegenerative diseases. Chris Li and Angela Hornsten at Boston University have used the nematode Caenorhabditis elegans to study Alzheimer’s disease.
A prominent feature of Alzheimer’s is the accumulation of dense, extracellular plaques in the brain. A major component of those plaques is a peptide called beta-amyloid. It forms from a larger molecule called amyloid precursor protein (APP).
Li says that the activities of APP in humans are unknown, but researchers have shown that a part of the molecule lies inside the cell, while another part projects through the membrane into the space between cells. That part is called the extracellular domain.
Li wants to know what the extracellular domain of APP is doing. Is it released to bind to a receptor on some other cell? Or does it perform some function in the environment outside the cell?
Such questions are hard to answer in complex mammalian systems, but genetic studies in simpler animals such as nematodes may locate interacting genes, leading to the identification of similar genes in higher animals.
Three APP-related genes have been discovered in mammals. C. elegans has only one, apl-1, which codes for the protein called APL-1.
Li and Hornsten found that the loss of apl-1 is lethal in nematodes. “Finding out how APL-1 functions and the domains of APL-1 that are important in the worm may help us understand which domains, cellular functions, and pathways are important for human APP,” Li says.
She has found that the functional part of the protein molecule lies neither in the cytoplasm nor in the cell membrane, as most researchers have assumed. Rather, it projects into the space outside the cell. C. elegans needs only that part of APL-1 in order to survive. Learning more about the extracellular domain of APL-1 may lead to a better understanding of how Alzheimer’s develops in humans.
Feany says she is excited about her fly model because it provides new directions for other researchers to explore. Li is equally enthusiastic.
“The best use of any of the model systems is the ability to collaborate and go back and forth between the model system and the mammalian system to test different hypotheses,” she says.