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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 gene that caused neurodegenerative disease 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 disorder," she said. "That made us realize that this could be a powerful approach to understanding more about how human disease happens."

The disorder 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 approach these complex human situations," she said. "The more ways we use simpler, manipulable, but highly conserved systems to obtain a better understanding of how these diseases happen and progress, the more progress can be made in developing ways to interfere with and treat these diseases."

Indeed, the fly can be used not only to provide insight into mechanisms of disease but also to develop insight into therapeutic approaches.

Bonini's lab subsequently found that a protein called Hsp70 can protect these genetically altered flies from the effects of the human polyglutamine repeat disease. Hsp70, called a molecular chaperone, helps to guard against the protein globs, preventing neural damage.

Bonini is also using fruit flies to study other human diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS). In 2002, she found that geldanamycin, an antibiotic, could prevent signs of Parkinson's disease in fruit flies that had been given the ?-synuclein gene. In humans, mutations in—or simply too much of—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 ?-synuclein. As a result, flies that would normally lose proper integrity of their dopamine-producing neurons due to deleterious effects of ?-synuclein, instead now had normal numbers of these neurons. Her more recent studies have shown how using the fly has revealed a common genetic risk factor for the human motor neuron disease, ALS.

Bonini's early research may have given her the idea to put human mutant disease genes into flies and define their pathways of destruction. 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 illustrated striking conservation of gene pathway function between mice and flies. This opened the door to the idea of using the fly to study the deleterious activity of critical human genes that cause disease, and then translating findings from the fly back to the human situation, providing the foundation for new approaches to treatment.