March 2, 2005
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
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 communication.
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
"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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