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 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 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 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," states Jongens.

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.

###

PENN Medicine is a $2.7 billion enterprise dedicated to the related missions of medical education, biomedical research, and high-quality patient care. PENN Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System (created in 1993 as the nation’s first integrated academic health system).

Penn’s School of Medicine is ranked #3 in the nation for receipt of NIH research funds; and ranked #4 in the nation in U.S. News & World Report’s most recent ranking of top research-oriented medical schools. Supporting 1,400 fulltime faculty and 700 students, the School of Medicine is recognized worldwide for its superior education and training of the next generation of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital, the Hospital of the University of Pennsylvania, consistently rated one of the nation’s “Honor Roll” hospitals by U.S. News & World Report; Pennsylvania Hospital, the nation's first hospital; Presbyterian Medical Center; a faculty practice plan; a primary-care provider network; two multispecialty satellite facilities; and home health care and hospice.

This release is available online at http://www.uphs.upenn.edu/news/News_Releases/mar05/fragx.htm