You may think that scientists know everything there is about antidepressant drugs such as Prozac or fluoxetine (its generic name). After all, these drugs have been around for a while. Fluoxetine-like antidepressants are known for their selective inhibition of proteins called serotonin transporters, which sequester the active neurochemical serotonin back into cells (thus the term SSRI or selective serotonin reuptake inhibitor). Surprisingly, it is still debatable whether this molecular activity of SSRIs is solely responsible for their therapeutic effects. Hence, molecular research typically conducted in a Petri dish or in experimental animals including worms (C. elegans) and fruit flies (Drosophila melanogaster) has been looking for alternative explanations.
Worms and fruit flies have proved useful whole-organism models for genetic research. More recently, these tiny animals have started to provide us with hints on the genetic mechanisms of human brain disorders and have become increasingly useful in the search for new molecular targets in drug discovery.
Some ten years ago, a group of geneticists stumbled upon the notion that Prozac makes worms wrinkle their noses. These scientists tried to find the molecular reason for this unexpected action of the drug. It turned out to be a gene family, which when mutated diminished the nose muscle contractions caused by Prozac. They named the gene family nose resistant to fluoxetine, or NRF. Scientists hoped that by identifying the proteins made by the worm NRF genes they would be able to find a corresponding human protein, which they could investigate as a new target of Prozac’s action, a target different from the already known serotonin transporter. Unfortunately there was no known human counterpart.
Dr. Svetlana Dzitoyeva from the University of Illinois at Chicago noted similarities between the DNA sequence of NRF genes and a sequence found in fruit fly DNA. She and colleagues hypothesized that this fruit fly DNA sequence could be a gene similar to NRF. If they could identify that fruit fly gene, they might be able to pinpoint its human counterpart and possibly discover a new target for antidepressant action.
Active genes make gene-specific messenger RNAs; these mRNAs lead to the production of corresponding proteins. Dzitoyeva and colleagues have developed a method for identifying new active genes in which they inject anesthetized fruit flies with molecules called dsRNA. These dsRNA molecules can be designed to destroy any particular mRNA. As a result, the injected fly loses its targeted endogenous mRNA. For all practical purposes, this treated fly would behave as if the corresponding gene was inactivated. Looking at the cellular or behavioral consequences of such gene silencing, scientists can tell what the function of the corresponding gene would be.
Dzitoyeva and colleagues designed a dsRNA against the fruit fly sequence similar to the worm nose resistant to fluoxetine and succeeded in finding a functional new fruit fly gene. They saw its activity in different tissues including the fly brain. Silencing this gene in fly embryos created a loss of developmental markers know as belts. So they named the new gene beltless.
Unfortunately, fruit flies differed from worms in that they did not have any obvious behavioral responses when given Prozac. There was no fly behavior that would correspond to the Prozac nose twitches in worms. Since Dzitoyeva and colleagues could not have investigated how the silencing of beltless would influence the effects of fluoxetine in fruit flies , their project lost momentum and was abandoned.
New life may be breathed into these old studies by recent developments that are searching for the human counterpart of the beltless gene and its possible role as a target for fluoxetine-like drugs. Improved annotation and recent characterization of the fruit fly genome revealed that the sequence of the beltless gene corresponds to a gene that had previously been predicted based on mutation studies and called drop-dead. Hence, beltless and drop-dead appear to be the same entity and are related to the worm nose resistant to fluoxetine.
Drop-dead mutant flies are initially normal but after some days, they begin to show deficits in flight, develop brain lesions, and rapidly die. The main deficit caused by the drop-dead mutation takes place in the white brain cells (glia). It was suggested that this gene normally produces proteins necessary for maintenance of the adult brain. This maintenance is often called neuroplasticity. Neuroplasticity is usually compromised during aging and may lead to neurodegeneration. Fluoxetine-like drugs are known to be capable of helping neuroplasticity. Hence, nose resistant to fluoxetine may be pointing to a new target for the action of antidepressants; a drop-dead-mediated neuroplasticity.