You may think that scientists know all things there is about antidepressant drugs such as Prozac or fluoxetine (its generic name). After all, these drugs have been nearby 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 either this molecular activity of Ssris is solely responsible for their therapeutic effects. Hence, molecular study typically conducted in a Petri dish or in experimental animals together with worms (C. Elegans) and fruit flies (Drosophila melanogaster) has been seeing 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 crusade for new molecular targets in drug discovery.
Some ten years ago, a group of geneticists stumbled upon the idea that Prozac makes worms wrinkle their noses. These scientists tried to find the molecular think for this unexpected activity 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 unyielding 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 study as a new target of Prozac's action, a target separate 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 recognize that fruit fly gene, they might be able to pinpoint its human counterpart and possibly seek 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 advanced a recipe 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. seeing 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 unyielding to fluoxetine and succeeded in seeing a functional new fruit fly gene. They saw its activity in separate tissues together with 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 sway the effects of fluoxetine in fruit flies, their project lost momentum and was abandoned.
New life may be breathed into these old studies by modern developments that are searching for the human counterpart of the beltless gene and its potential role as a target for fluoxetine-like drugs. Improved criticism and modern characterization of the fruit fly genome revealed that the sequence of the beltless gene corresponds to a gene that had previously been expected 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 unyielding to fluoxetine.
Drop-dead mutant flies are initially normal but after some days, they begin to show deficits in flight, make 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 ordinarily produces proteins important for maintenance of the adult brain. This maintenance is often called neuroplasticity. Neuroplasticity is ordinarily compromised while aging and may lead to neurodegeneration. Fluoxetine-like drugs are known to be capable of helping neuroplasticity. Hence, nose unyielding to fluoxetine may be pointing to a new target for the activity of antidepressants; a drop-dead-mediated neuroplasticity.
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