Potential Treatment for Fragile X Syndrome Demonstrated
in Fruit Fly Model
(Philadelphia) - Fragile X Syndrome is one of the most commonly inherited
forms of mental retardation, with an incidence of 1 in 4,000 males and
1 in 8,000 females. Not many medications exist to help Fragile X patients.
Now, in a fruit fly model of the disease, researchers from the University
of Pennsylvania School of Medicine and their colleagues have
shown that it is possible to reverse some of the symptoms of the disorder
using drugs that dampen specific neuronal overactivity. Their findings
appear in the March 3, 2005 issue of Neuron.
Characteristics of Fragile X in people include an average IQ of about
50, deficits in certain types of short-term memory, autistic behavior,
sleep problems, hyperactivity, attention deficits, and susceptibility
to seizures. In humans, Fragile X syndrome is caused by the FMR1
gene not working properly or at all. This gene encodes the FMRP protein,
which controls the availability of select proteins involved in neuron-to-neuron
Senior author Thomas A. Jongens, PhD, Associate Professor
of Genetics at Penn, and colleagues from Albert Einstein College of Medicine
and Drexel University College of Medicine, as well as other labs, have
developed and characterized a Drosophila fly model for Fragile
X. This model is based on mutants that lack the dfmr1 gene, which
encodes a protein similar to human FMR1 protein. "Interestingly,
work by my lab and others have found that the dfmr1 mutants display
many physical and behavioral characteristics similar to symptoms displayed
by Fragile X patients," says Jongens. These include structural defects
in certain neurons, enlarged testes, failure to maintain proper day/night
activity patterns; attention deficits and hyperactivity, and defects in
behavior-dependent learning and memory.
"Our thinking was that since so many of the behavioral and physical
phenotypes in the fly model were similar to symptoms observed in fragile
X patients and a mouse fragile X model, FMR1 and dfmr1 must be
regulating similar biological processes in human, mice, and flies,"
A mouse model of Fragile X also shows symptoms similar to those of Fragile
X patients. Studies outside of Penn using the mouse model have demonstrated
that Fragile X patients have a tendency to break down synaptic connections
(sites used for neuron to neuron communication) more readily than the
general population. This breakdown is due to an increased activity in
the metabotropic glutamate receptor (mGluR), which is located on the surface
of neurons, including in the hippocampus – the memory and learning
center in the brain. In turn, this increased activity compromises neurotransmission
for memory-associated functions.
Jongens and colleagues surmised that mGluR overactivity may be at the
root of many of the Fragile X symptoms. Using such drugs as lithium chloride
and others, known as antagonists, that block mGluR's activity, the team
tested to see if the drugs could rescue any of the observed behavioral
and memory defects observed in the fly model.
"What we found was very striking," says Jongens. They found
that the drug treatments restored memory-dependent courtship behavior
in mutant flies and reversed some of the neuronal structural defects.
The group used lithium because it is known to have activities analogous
to blocking mGluR-receptor activity, and it is already an FDA-approved
drug used to treat other ailments in humans such as bipolar disorder.
"The big take-home message from our work is that maintaining proper
regulation of mGluR signaling is a conserved function of the dFMR1 and
FMRP proteins and that loss of dfmr1 function in flies leads to at least
a subset of the cognitive and behavioral defects observed in the fly model,"
says Jongens. "These results provide a potential route by which symptoms
of Fragile X patients may be ameliorated."
First authors on the paper are Sean M.J. McBride, Albert Einstein College
of Medicine, and Catherine H. Choi, Drexel University College of Medicine.
This work was funded by the National Institutes of Health and the FRAXA
Research Foundation, Newburyport, MA.
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