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Mutant gene discovery may provide insight to neurodegenerative disease
September 18, 2006

by Nicole Miller

The discovery of a mutant gene in fruit flies will likely provide scientists with a useful model to study neurodegenerative diseases in humans such as Alzheimer's and Parkinson's diseases and amyotrophic lateral sclerosis (ALS).

The mutant gene, named "wasted away," also has a direct human counterpart that leads to a lesser-known neurodegenerative disorder. These findings were reported today (Sept. 18) in the Proceedings of the National Academy of Sciences.

The gene was identified in fruit flies sensitive to temperature. At higher-than-normal temperatures, the mutant flies become paralyzed. "These mutant flies lose motor activity, so there is an obvious neural impairment. They also manifest holes in the brain, which is evidence of neurodegeneration, and die much sooner than normal flies," says University of Wisconsin-Madison geneticist Barry Ganetzky, one of the paper's authors. "Clearly, there is something wrong with the nervous system."

Ganetzky, along with UW-Madison colleagues Joshua Gnerer, a genetics graduate student, and Robert Kreber, a research specialist in the same department, then proceeded to map, clone and identify the gene. "The gene turned out to encode a protein called triosephosphate isomerase (Tpi) that is the exact protein involved in a known human neurodegenerative disorder," says Ganetzky, who is also a National Academy of Sciences member and an American Association for the Advancement of Sciences fellow.

The related human disorder caused by the same aberrant protein, known as Tpi deficiency, is rare and not well understood. In humans, neurological symptoms first appear between six months and 2 years of age, and death generally occurs by age 6. The mutant fruit flies show similar symptoms and provide scientists with an excellent model to study this lethal disorder.

Many neurodegenerative disorders are characterized by the presence of misfolded proteins and protein aggregates inside affected nerve cells, including Alzheimer's and Parkinson's. Protein aggregates are made up of misfolded proteins that stick together and no longer function properly. Although proteins are necessary for the proper function of brain cells, when they aggregate into clumps they are generally considered unhealthful.

Scientists have studied these aberrant proteins for years, but many questions remain about how aggregates form inside neurons and the role of misfolded and aggregated proteins in the progression of neurodegenerative diseases.

Some researchers working on Tpi deficiency in humans propose that this disorder happens when aberrant Tpi proteins directly misfold or aggregate. But one research team has proposed an alternative explanation, believing that the effect of the defective Tpi protein is indirect. Findings from Ganetzky's team support the latter explanation.

"We think that the protein is a defective, underperforming enzyme," says Ganetzky. Inside the cell, enzymes are responsible for aiding in a wide variety of chemical reactions. Normally, the job of the Tpi protein is to convert a molecule known as DAPH into a second compound used in metabolism. However, when the Tpi protein is not functioning at full speed, a bottleneck occurs and DAPH accumulates inside the body, a phenomenon that has been shown in studies of human patients with Tpi deficiency.

"While there is no evidence that DAPH itself is toxic, it spontaneously converts to methylglyoxal, which is toxic to neurons," explains Ganetzky. "Methylglyoxal chemically modifies proteins with various consequences. It leads to the loss of activity of proteins. It leads to cross-linking of proteins. It leads to protein aggregation."

Thus, Ganetzky and his colleagues believe that methylglyoxal — and the various proteins it modifies — likely cause the defects in neuronal function and viability associated with Tpi deficiency, and that methylglyoxal may similarly contribute to other neurodegenerative disorders.

"There is a lot of evidence to suggest that methylglyoxal could be, at the very least, an important contributing factor [to many neurodegenerative diseases]," says Ganetzky. "So, not only do we have a very useful experimental model to study Tpi deficiency in humans, but we have an experimental system in which we can study the role of methylglyoxal in a broader biological context — as it relates to other neurological disorders such as Alzheimer's, Parkinson's, Huntington's and ALS."

In the future, Ganetzky's mutant fruit flies may prove to be a useful organism for testing new drugs that may one day help prevent neurodegenerative diseases that are caused by methylglyoxal toxicity.

More immediately, says Ganetzky, the next step is to prove their fly model by confirming high levels of DAPH and methylglyoxal in the mutant flies. He and his team also plan to reverse the effects of the "wasted away" fruit fly mutation by genetically adding a protein that can detoxify methylglyoxal and alleviate symptoms of disease in the mutant fly.

This research was supported by the National Institutes of Heath.

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