By David N. Leff

Next time you swat a fruit fly (Drosophila melano-gaster) buzzing around a bowl of cherries, remember you're killing one of man's best friends - which today is getting friendlier.

"There are about 17,000 genes in the Drosophila genome," said neurogeneticist Juan Botas, at Baylor College of Medicine, Houston. "This is substantially less than the number of genes in the mouse or in humans. But the difference in numbers is misleading," he added, "because in the mammalian genome - the human genome - the number is higher mostly because each of the genes in Drosophila has been copied several times over. So even though there are many more genes in humans, they are really variations of the same genes already existing in the fly."

So Botas turned to D. melanogaster - already a century-old, seminal, poster insect of genetic research - for a foray into the genetic basis of neurodegenerative diseases. He chose as his model spinocerebellar ataxia (SCA) - which features uncontrolled muscle activity during voluntary movement. Its stumbling, staggering gait afflicts an estimated one to four live births worldwide.

Among the neurodegenerative disorders that loom so large in contemporary society, SCA shares a striking root cause with Huntington's disease (HD). Both harbor mutant neurons in the brain that express the essential amino acid glutamine non-stop. SCA's ataxin gene consists of three genomic bases - cytosine-adenine-guanine (CAG). That triplet CAG codon, hallmark of both SCA and HD, repeats endlessly to pile up glutamine in the hapless neurons. CAG accounts for the horrendous, though differing, manifestations of both diseases. (See BioWorld Today, June 4, 1998, p. 1.)

Alzheimer's and Parkinson's diseases are another story, but relevant.

"Our reason for modeling this cerebellar ataxiain Drosophila," Botas noted, "is that in the fruit fly we can do large screenings, looking for genes that when their activity is altered, suppress or otherwise modify neurodegeneration. We looked at thousands of genes in the Drosophila genome. That kind of high throughput is not possible in mice - for practical reasons. You cannot screen thousands of different mutant mice to see what genes might be causative or involved in disease progression."

Sifting Through Fruit Flies' Myriad Genes

"You can do that in flies," he said, "and in a short time. That also facilitates the screening, because there are fewer targets to look into. So our strategy was to find out what fly genes are implicated, and then perhaps go back to mice. Basically, our idea is to spearhead the discovery of new relevant genes in an amenable system like Drosophila."

Botas is senior author of a progress report in today's Nature, dated Nov. 2, 2000, and titled: "Identification of genes that modify ataxin-1-induced neurodegeneration."

"We created our model system," he told BioWorld Today, "by expressing the full-length human SCA gene in Drosophila's genome." Then, he said, "we did two screens. One of them looked for genes that modify neurodegeneration when we reduce their activity. We screened about 3,000 genes that way.

"The second screen," Botas added, "was a little different: Instead of asking what genes are there that - when we reduce their activity - modify the degeneration, we asked what genes modify the degeneration when, instead, we increase the activity. So we went both ways - reducing activity, increasing activity.

"In those two screens," he went on, "we found suppressors - genes able to suppress or slow neurodegeneration - and also genes that aggravated the neuronal death. Those are also interesting because they can identify for us what pathways are involved in the neurodegeneration process."

The co-authors identified five classes of genes, the last three discovered by Botas:

¿ One encoded a chaperone molecule involved in protein folding.

¿ A second class, implicated in proteolysis, encoded components of the machinery of the cell that takes care of eliminating abnormal proteins.

¿ The third class of genes is involved in cellular detoxification, and the elimination of free radicals and other chemical compounds that are toxic to the cells.

¿ The fourth new pathway included certain genes involved in transcriptional regulations.

¿ The fifth in RNA processing.

"Every single gene that we found," Botas noted, "has an equivalent, homologous gene in humans."

Fruit flies rendered transgenic for the human SCA-1 gene don't develop ataxia. Rather, their eyes reflect the genetic insult. "What we did in Drosophila," Botas said, "was to establish an assay for neuronal degeneration. Expressing the faulty human genes triggered the start of the neurodegenerative process, and as an end result, the death of the neurons. We tried to fill in that gap between the trigger and the neuronal-death endpoint. We determined that fly neurons degenerated more rapidly in the case of genes that aggravated. Conversely, in the case of the genes that suppress, those dying neurons slowed down."

The Baylor team measured these changes in Drosophila's two bulging eyes. Each of those compound orbs consists of some 800 single units called ommatidia. "The reason we did that," Botas explained, "is that the eye is an organ with many neurons, and very easy to score a change in the phenotype. It provides us with a very quick and fast assay. The defects we saw in the eye were a consequence of the cells in which we expressed the faulty genes."

In The Act: Alzheimer's and Parkinson's

Botas sees similarities between the CAG-repeat mutant proteins of SCA and HD and the defective proteins - synuclein in Parkinson's, amyloid precursor in Alzheimer's diseases. "It is conceivable," he said, "that the mechanisms involved in neurodegeneration are similar. We are planning to test that directly."

Botas is principal inventor of patent applications filed by the Medical College. "A big question mark," he said, "is how do we use these findings to get a step closer to treating the diseases? That means developing compounds that could alter the activity of these proteins, recapitulating the suppressor alteration that we made by manipulating the genes. That's something we cannot do in patients. But drugs can do it at the level of proteins." That, he concluded, "is really what we have to go into."

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