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Fixing Fragile X
by Sarah C.P. Williams
Knocking out a single gene in neurons eliminates symptoms of fragile X syndrome in mice.
The connections between neurons in the brain hold a surprising clue to fragile X syndrome.
By probing the network of genes and proteins active at the junctions between neurons in the brain, HHMI researchers have unearthed a new strategy for treating fragile X syndrome—the most common inherited form of mental retardation.
Mark Bear, an HHMI investigator at the Massachusetts Institute of Technology, studies how the connections between neurons are strengthened or weakened as new pieces of information are retained in the brain, and other memories fade. He previously found that a neurotransmitter receptor called mGluR5 plays a role in weakening neural connections, by increasing the amount of proteins made at the synapses between neurons.
Most recently, Bear discovered that fragile X mental retardation protein (FMRP), which is mutated in fragile X syndrome, counterbalances mGluR5. “The fragile X protein is normally putting a brake on the protein synthesis stimulated by mGluR5,” explains Bear. This means that in fragile X syndrome, FMRP is not around so the protein synthesis goes unchecked.
Bear and his colleagues, in a study published in the December 20, 2007, issue of Neuron, showed that getting rid of one copy of mGluR5 in fragile X-affected mice eliminates the seizures and memory impairments that such mice typically exhibit.
The researchers bred mice with fragile X syndrome—characterized by developmental delay, structural changes in the brain, and epilepsy—with mice engineered to produce half the normal level of mGluR5. Their offspring showed few symptoms of fragile X, despite the mutation in FMRP they had inherited.
Since mGluR5 and FMRP do not directly interact, but influence neural protein synthesis in opposite directions, the results suggest that it is the increased protein synthesis in fragile X patients that leads to the syndrome. The brains of fragile X-affected mice typically have an excess of particularly weak neural connections. Bear hypothesizes that the increased protein synthesis could be leading to this high density of connections.
“Now we have a lot of work ahead of us to figure out which proteins are producing the pathology,” says Bear, who is also now studying whether blocking mGluR5 receptors in humans can counter fragile X syndrome.
Photo: James Cavallini / Photo Researchers, Inc.