New Screening Method Shows Promising Drug Targets for Fragile X Syndrome

By using a new drug screening method in Drosophila (fruit flies), researchers have identified several drugs and small molecules that reverse the features of fragile X syndrome - a frequent form of mental retardation and one of the leading known causes of autism.

According to the research team, led by Stephen Warren, PhD, chair of the Department of Human Genetics at Emory University School of Medicine, the finding sets the stage for developing new treatments for fragile X syndrome.

In 1991, Dr. Warren and his team discovered the FMR1 gene responsible for fragile X syndrome. Fragile X syndrome is caused by the functional loss of the fragile X mental retardation protein (FMRP).

In the new study, the researchers used a Drosophila model lacking the FMR1 gene.

These fruit flies have abnormalities in brain structure and behaviour that is similar to abnormalities in the human form of fragile X syndrome.

When fly embryos lacking FMR1were fed food containing increased levels of glutamate, they died during development, which is consistent with the theory that the loss of FMR1 results in excess glutamate signalling.

The researchers placed these embryos in thousands of tiny wells containing food with glutamate. Also, each well contained one compound from a library of 2,000 drugs and small molecules.

Using this screening method, the researchers found nine molecules that reversed the lethal effects of glutamate.

The three newly found compounds were known activators of GABA, a neural pathway already known to inhibit the effects of glutamate.

The researchers found in their study that GABA reversed all the features of fragile X syndrome in the fruit flies, including deficits in the brain's primary learning center and behavioural deficits.

The screening method also helped researchers in identifying other neural pathways that might have a similar role in fragile X syndrome and could be targets for drug therapy.

"Our discovery of glutamate toxicity in the Drosophila model of fragile X syndrome allowed us to develop this new screen for potential drug targets," Nature quoted Dr. Warren, as saying.

"We believe this is the first chemical genetic screen for fragile X syndrome, and it highlights the general potential of Drosophila screens for drug development.

"Most importantly, it identifies several small molecules that significantly reverse multiple abnormal characteristics of FMR1 deficiency. It also reveals additional pathways and relevant drug targets. These findings open the door to development of effective new therapies for fragile X syndrome," he added.

The study is published online in the journal Nature Chemical Biology.

Source-ANI
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