Piecing Together a Fragile-X Puzzle

Scientists have discovered why a single mutated protein can lead to serious mental retardation in men with a common genetic disorder called fragile-X syndrome: The healthy protein is essential for establishing during childhood the adult pattern of connections between nerve cells in the brain. The finding, reported in tomorrow's issue of the Proceedings of the National Academy of Sciences, may help researchers narrow their search for a possible therapeutic drug against a condition that strikes one in 2000 male births.

Researchers had long suspected that fragile-X syndrome--named for the broken appearance of the X chromosomes--resulted in faulty connections between neurons, called synapses. One of the first clues came from autopsies of people with fragile-X; their brains had immature synapses, suggesting a missing protein. The trail warmed in the early 1990s when researchers determined that, in normally developing brains, neurotransmitters triggered protein production near synapses.

William Greenough, a neuroscientist at the University of Illinois, Urbana-Champaign, decided to peer more closely at proteins forming near the synapse. Using filters and centrifuges, his team isolated the synaptic portions of dendrites--the short, receiving ends of nerve cells--from thousands of rat neurons. They stimulated some of them in test tubes with the neurotransmitter glutamate and, with a technique called a Northern blot, caught the messenger RNA--the genetic template from which proteins are made--in the act of fabricating proteins. When the researchers compared the mRNA to a library of DNA sequences taken from the dendrites of neurons by James Eberwine of the University of Pennsylvania Medical Center, they found that it came from a single gene on chromosome X--the human version of which, when mutated, leads to fragile-X syndrome.

To probe this gene's role in brain development, Greenough's collaborators at the University of Amsterdam and at Erasmus University in Rotterdam, the Netherlands, knocked out the gene in mice. They found that dendrites in adult mouse brains were studded with long spines, a hallmark of immature neurons. During normal development, a stimulated neuron develops fat and short spines (which are thought to transmit signals better), while underused spines on the dendrites wither. Greenough speculates that without the fragile-X protein, not enough synapses die and the brain ends up crowded with immature and noisy neurons.

"It's an extremely provocative finding," says Oswald Steward, a neuroscientist at the University of Virginia Health Sciences Center in Charlottesville. But it's unclear whether the fragile-X protein itself is crucial for nerve development or whether it tells other proteins to do the job. Either way, a drug that replaces the aberrant protein might counteract an otherwise devastating condition.

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