It may seem futile to use fruit flies to study complex human conditions such as Parkinson's, Alzheimer's, and Huntington's disease. It's a good thing Nancy Bonini didn't think so.
In 1998, Bonini's group published astonishing results: they put a human neurodegenerative disease gene into a fruit fly and recreated the effects of the disease.
"We were stunned at the degree to which the fundamental features of the fly disease really looked like the human disease," she said. "That made us realize that this could be a powerful approach to understanding more about how human disease happens."
The disease the group recreated is called spinocerebellar ataxia type 3, or Machado-Joseph disease (SCA3/MJD). It's one of about nine conditions—Huntington's disease is another—known as polyglutamine repeat diseases. In these conditions, a gene produces a protein with too many copies of an amino acid called glutamine. The resulting extra-long domain of glutamine makes the protein form globs that destroy cells, leading to neurological problems and ultimately to death.
Bonini's breakthrough idea has stimulated many labs to do similar experiments with other human disease genes and in other model organisms, including Caenorhabditis elegans (a nematode) and yeast.
"You need a myriad of systems to know that what you're studying is relevant to a human situation," she said. "The more ways we can try to get at an understanding of how these diseases happen, the better off we are."
Bonini's lab also has found that a protein called Hsp70 can protect these genetically altered flies from the effects of polyglutamine repeat disease. Hsp70, called a molecular chaperone, helps to protect against the protein globs, preventing neural damage.
Bonini also is using fruit flies to study Parkinson's disease. In 2002, she discovered that geldanamycin, an antibiotic, could prevent signs of the disease in fruit flies that had been given a faulty form of the α-synuclein gene. In humans, mutations in this gene have been linked with movement disorders and the buildup of deposits called Lewy bodies in the brain, hallmark characteristics of Parkinson's disease. Bonini found that geldanamycin ramped up the activity of the stress response, and protected neurons from the effects of α-synuclein. As a result, flies that would normally lose proper integrity of half of their dopamine-producing neurons due to expression of α-synuclein, instead now had normal numbers of these neurons.
Bonini's early research may have given her the idea to test the function of human genes in fruit flies. Her work involved eyes absent, a gene that controls eye development: fruit flies without the gene have no eyes. Among other experiments, she took eyes absent counterpart genes from mice and put them into the fly, to see if they could rescue the fly mutant lacking the eyes absent gene. The hatched flies developed with normal eyes, showing that eyes absent genes performed similarly across the two species. These studies, which illustrated striking conservation of gene function between mice and flies, opened the door to the idea of using the fly to study the function of critical human genes that cause disease.
