Frontiers

A Fly's Perspective on the Human Brain

Biologist Nancy Bonini uses fruit flies to shed light on neurodegenerative diseases.
December 2008

From high school biology classes to the laboratories of Nobel Prize-winning geneticists, the halls of science have long valued the Drosophila melanogaster—the common fruit fly. Despite appearances to the contrary, this tiny insect is a powerful genetic model for the human system. One reason for this, explains Nancy Bonini—Lucille B. Williams Term Professor of Biology and an investigator of the Howard Hughes Medical Institute—is that Drosophila and Homo sapiens share a great many of the same genes. And, because fruit flies have a life cycle of about 10 days, it is possible to study the progression of genetic diseases and track mutant genes across generations in a highly compressed time scale.

“These diseases take decades to develop in humans, and take months to years in mice,” Bonini says.  “In flies, we’re talking days—it really puts time on our side.”

For many years, Bonini’s own lab has been using the fruit fly to address fundamental mechanisms in long-term maintenance of brain function and neurodegeneration in humans. When Bonini first joined Penn, the fly had long been used to study fundamental aspects of human development, but it hadn’t been used extensively as a model to explore neurodegenerative diseases. Along with researchers from Penn’s School of Medicine, she devised an experiment that successfully implanted into Drosophila the gene that causes SCA3 (spinocerebellar ataxia type 3) and created transgenic flies that displayed symptoms of the human disease.

SCA3 is a hereditary neurodegenerative disease that typically strikes in mid-life and causes degeneration in the ability to control muscular movement. It belongs to a class of progressive, late-onset neurodegenerative diseases, including Huntington’s, called polyglutamine repeat disorders. In these disorders, instructions for producing the amino acid glutamine are repeated excessively in a coding region of the DNA. Normally, the sequence of three nucleotides that specify glutamine—cytosine, adenine and guanine (CAG)—is repeated 15 to 20 times. In those suffering from SCA3, the sequence has been found to repeat as many as four times more than the normal number. The result is the creation of misfolded proteins that accumulate in the cells of the nervous system and disrupt cellular operations.

Bonini’s experiments succeeded in producing mutant flies with the same toxic protein in their brain cells, confirming that the affliction proceeds by similar mechanisms in the fly as it does in humans. By developing the first model of human neurodegenerative disease in Drosophila, Bonini set the stage for a new avenue of research on not only polyglutamine repeat diseases, but other neurodegenerative diseases like Alzheimer’s and Parkinson’s.

“The idea of using the fly and other simple systems to approach the huge problem of human neurodegenerative disease has really taken off at Penn and elsewhere,” Bonini explains.

This year, Bonini published findings that show that faulty RNA containing a long CAG repeat may contribute to neurodegeneration in polyglutamine repeat disorders beyond only being the blueprint for misfolded proteins. In performing a genetic screen for potential contributors to the synthesis of ataxin-3, the toxic protein associated with the SCA3 disease, Bonini and her team identified a new gene that dramatically enhanced neurodegeneration. This gene, while not previously implicated in polyglutamine repeat disorders, was known to contribute to other classes of diseases that were due to toxic RNA. “This suggested that what’s coding for the toxic proteins also has a toxicity of its own that causes problems,” says Bonini.

She and her team then conducted an experiment in which they created the ataxin-3 protein with RNA that did not use the long CAG repeat sequence. They found that although the protein produced was identical, the altered gene resulted in dramatically reduced neurodegeneration, thus implicating the RNA sequence in the disease progression. Bonini and her team then expressed, in Drosophila brains cells, RNA with the long CAG repeat sequence that was unable to code for a protein. They found that neuronal degeneration occurred even without the presence of the protein.

Bonini says one reason this finding is interesting is because it suggests commonalities between polyglutamine repeat diseases and other diseases that are thought to be due to just RNA toxicity.

“If it’s possible to find a therapeutic that works against one of these other categories of diseases, it may also work for polyglutamine repeat diseases, and vice versa, because they both have a toxic RNA component,” Bonini explains. “It also emphasizes the need for therapeutics that could hit both the protein and RNA, thereby attacking multiple components of the toxicity.”

Bonini’s current research focuses on identifying the mechanisms behind toxic RNA. “The field of RNA biology has exploded in the past 10 years, and it’s a whole new world,” she says. “My research is just the tip of the iceberg of our knowledge about how problems with RNA can cause diseases.”