 |
|
Drosophila drug screen for fragile X syndrome finds promising compounds and potential drug targets
March 10, 2008Scientists using a new drug screening method in Drosophila (fruit flies), 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. The discovery sets the stage for developing new treatments for fragile X syndrome.
The results of the research by lead scientist Stephen Warren, PhD, chair of the Department of Human Genetics at Emory University School of Medicine, are published online in the journal Nature Chemical Biology.
Dr. Warren led an international group of scientists that discovered the FMR1 gene responsible for fragile X syndrome in 1991. Fragile X syndrome is caused by the functional loss of the fragile X mental retardation protein (FMRP). Currently there is no effective drug therapy for fragile X syndrome, and previously no assays had been developed to screen drug candidates for the disorder.
During the past 17 years, intense efforts from many laboratories have uncovered the fundamental basis for fragile X syndrome. Scientists believe FMRP affects learning and memory through regulation of protein synthesis at synapses in the brain. One leading view, proposed by Dr. Warren and colleagues, suggests that over stimulation of neurons by the neurotransmitter glutamate is partly responsible for the brain dysfunction resulting from the loss of FMRP.
In their current experiment, Emory scientists used a Drosophila model lacking the FMR1 gene. These fruit flies have abnormalities in brain architecture and behavior that parallel abnormalities in the human form of fragile X syndrome. When FMR1-deficient fly embryos were 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 signaling.
The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. Using this screening method, the scientists uncovered nine molecules that reversed the lethal effects of glutamate.
The three top identified compounds were known activators of GABA, a neural pathway already known to inhibit the effects of glutamate. In the study, GABA reversed all the features of fragile X syndrome in the fruit flies, including deficits in the brain's primary learning center and behavioral deficits. The screening also identified other neural pathways that may have a parallel 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," notes Dr. Warren. "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."
Emory University
During the past 17 years, intense efforts from many laboratories have uncovered the fundamental basis for fragile X syndrome. Scientists believe FMRP affects learning and memory through regulation of protein synthesis at synapses in the brain. One leading view, proposed by Dr. Warren and colleagues, suggests that over stimulation of neurons by the neurotransmitter glutamate is partly responsible for the brain dysfunction resulting from the loss of FMRP.
In their current experiment, Emory scientists used a Drosophila model lacking the FMR1 gene. These fruit flies have abnormalities in brain architecture and behavior that parallel abnormalities in the human form of fragile X syndrome. When FMR1-deficient fly embryos were 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 signaling.
The scientists placed the FMR1-deficient fly embryos in thousands of tiny wells containing food with glutamate. In addition, each well contained one compound from a library of 2,000 drugs and small molecules. Using this screening method, the scientists uncovered nine molecules that reversed the lethal effects of glutamate.
The three top identified compounds were known activators of GABA, a neural pathway already known to inhibit the effects of glutamate. In the study, GABA reversed all the features of fragile X syndrome in the fruit flies, including deficits in the brain's primary learning center and behavioral deficits. The screening also identified other neural pathways that may have a parallel 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," notes Dr. Warren. "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."
Emory University
Drosophila Current Events and Drosophila News RSSSchizophrenia gene's role may be broader, more potent, than thought
UCSF scientists studying nerve cells in fruit flies have uncovered a new function for a gene whose human equivalent may play a critical role in schizophrenia.
Deciphering the regulatory code
Embryonic development is like a well-organised building project, with the embryo's DNA serving as the blueprint from which all construction details are derived.
UM Scientists Create Fruit Fly Model to Help Unravel Genetics of Human Diabetes
As rates of obesity, diabetes, and related disorders have reached epidemic proportions in the US in recent years, scientists are working from many angles to pinpoint the causes and contributing factors involved in this public health crisis.
Circadian surprise: A heat sensor for body-clock synchronization
New research on the fruit-fly brain points to a possible mechanism by which temperature influences the body clock, according to scientists from Queen Mary, University of London.
Researchers discover mechanism that prevents two species from reproducing
Cornell researchers have discovered a genetic mechanism in fruit flies that prevents two closely related species from reproducing, a finding that offers clues to how species evolve.
A solution to Darwin's 'mystery of the mysteries' emerges from the dark matter of the genome
Biological species are often defined on the basis of reproductive isolation. Ever since Darwin pointed out his difficulty in explaining why crosses between two species often yield sterile or inviable progeny (for instance, mules emerging from a cross between a horse and a donkey), biologists have struggled with this question.
Fruit fly pest identified in wine grapes
A newly recognized pest in Oregon continues to concern fruit growers and researchers with the recent discovery of a Spotted Wing Drosophila fly in a sample of Willamette Valley wine grapes.
A balancing act in Parkinson's disease: Phosphorylation of alpha-synuclein
Both genetic and pathologic data indicate a role for the neuronal protein alpha-synuclein in Parkinson disease.
Reactive oxygen in fruit flies acts as a cell signalling mechanism for immune response
For years, health conscious people have been taking antioxidants to reduce the levels of reactive oxygen in their blood and prevent the DNA damage done by free radicals, which are the result of oxidative stress. But could excessive use of antioxidants deplete our immune systems?
Pesky fruit flies learn from experienced females: Study
A common household nuisance, the fruit fly, is capable of intricate social learning much like that used by humans, according to new research from McMaster University.
More Drosophila Current Events and Drosophila News Articles
 |
Drosophila: A Laboratory Handbook by Michael A. (Author), M.D. Ashburn (Author), Kent G. Golic (Author), R. Scott Hawley (Author) The second edition of the highly successful "grey book" Drosophila: A Laboratory Handbook, first published in 1989, has been completely updated to reflect advances in techniques and knowledge. The original format is maintained, providing a handy reference guide to most aspects of the biology of Drosophila. Each of the thirty–six chapters summarizes the present state of the subject, written with a historical perspective, but with an emphasis on the practical use of genetic and other methods. Extensively referenced. |
 |
Drosophila: Methods and Protocols (Methods in Molecular Biology) by Christian Dahmann (Editor) "Drosophila" is a comprehensive collection of methods and protocols for Drosphila, one of the oldest and most commonly used model organisms in modern biology. The text presents a diverse set of techniques that range from the basic handling of flies to more complex applications, such as the generation of mutants by homologous recombination and the analysis of developing flies by live imaging. Review chapters provide concise overviews of selected experimental systems. Drosophila is the perfect reference manual for Drosphila researchers. The straightforward presentation of Drosophila protocols will bolster successful experimental design and lead to reproducible results, and the troubleshooting tips are an invaluable aid for researchers at all levels. "Drosophila" will advance the use of... |
 |
Biology of Drosophila by M. Demerec (Editor) |
 |
SpringStar - Kitchen Fruit Fly Trap by SpringStar SpringStar's fruit fly trap is an excellent way to trap fruit flies that invade your home. There are no poisons or pesticides needed to accomplish this, just our unique and innovative trap. The patented lure attracts them into the trap with a combination of food grade scents. Once in the trap, they cannot get out. Safe to use around the house. |
|
Applied Scientific Drosophila Supplies: Petri Dishes; 60 x 15mm; Vented by Parter Medical Products Dishes, Disposable Petri; Applied Scientific; Vented, Flat, Uniform thickness; Sterile; 60 dia. x 15mmH | |
 |
Determined Drosophila Hoodie (dark) by CafePress |
 |
Drosophila Sun Project (Primary Contributor) |
 |
Pastilha Efervescente by Drosophila Second album of the quartet formed by Ana Luiza Pimentel (vocal and guitar), Elaine Jardim (bass), Rodrigo Palmieri (drums and vocal) and AndrZ Dias (guitar). Drosophila is a vigorous power pop with influences of Breeders, Pixies and Pave |
 |
Biologix Drosophila Bottles, Tray Pack, 200/cs by Biologix Research Features of the Biologix Drosophila Bottles: Made of high quality polypropylene with good visibility. The bottle capacity is 6 oz (177ml) with dimensions of 57L x 57W x 103mmH. Square Bottom, Disposable, and Autoclavable. Graduations are molded. The product referenced on this detail page is sold be 200/cs. |
 |
Fly Pushing: The Theory and Practice of Drosophila Genetics by Ralph J. Greenspan (Author) Experiments with Drosophila give investigators the chance to combine molecular and genetic approaches in studies of gene expression, cell function, and development. Fly genetics has a large and complex folklore that, for the uninitiated, is quite daunting. In this eagerly awaited book, Ralph Greenspan provides a bridge to that folklore. Entertaining and lucid, he guides the reader carefully through the practicalities of making crosses, isolating variants, mapping genes, constructing specific genotypes, and analyzing mutations. No previous knowledge of fly genetics is assumed. The techniques used are illustrated, and practice problems and solutions are included to assist the reader. This is an affordable and uniquely valuable book, ideal for graduate students starting projects... |
| © 2009 BrightSurf.com |