Troublesome Templates

It's bad enough to know you could pass on a genetic form of mental retardation to your children. But carriers of a Fragile X syndrome "premutation" have something else to worry about: They're at higher risk of neuromuscular degeneration. Now a new study explains why.

People with Fragile X syndrome--the most common inherited type of mental retardation--lack a protein called FMR1 because the gene for FMR1 is laden with extra DNA. The letters CGG repeat themselves more than 200 times, compared to fewer than 60 repeats in normal people. Premutation carriers have intermediate numbers of repeats. Clinicians have recently discovered that some of these people develop muscle tremors that worsen with age, similar to individuals with neuromuscular disorders. But doctors don't understand why.

Stephen Warren of Emory University in Atlanta and colleagues suspected that the neurodegeneration is caused by messenger RNA (mRNA) that serves as the template for the protein. They noted that muscle nerves don't degenerate in Fragile X patients, whose FMR1 gene is so long that mRNA is never even made. Carriers, however, make mRNA for FMR1 that carries between 60 and 200 repeats of CGG, but don't make the protein. To determine whether the premutation carriers' mRNA wreaks havoc on neurons, Warren's team turned to the fruit fly retina, which many researchers use to model degenerating nerves.

The team engineered FMR1 mRNAs containing zero, 60, or 90 repeats that couldn't be copied into protein. Overproducing the mRNAs in the fly retina, the researchers found that the longer the CGG repeat, the greater the neurodegeneration of retinal neurons. And in flies with more repeats, neurons died at a faster clip with age, Warren's team reports in the 28 August issue of Neuron. Another set of experiments suggested that things go awry when the mRNA clings to proteins inside neurons, perhaps due its length and stickiness. When the team made the flies overproduce a housecleaning protein that sweeps up misformed proteins, the neurodegeneration was prevented.

The findings "unequivocally" show that the neurodegeneration in premutation carriers is due to an mRNA defect, says neurogeneticist Huda Zoghbi of Baylor College of Medicine in Houston, Texas. The "big surprise," she adds, is that the mRNA apparently conspires with proteins. Although the identity of those proteins is unknown, identifying them may lead to a better understanding of other neurodegenerative diseases, she says.

Warren's site
Information on Fragile X syndrome from the National Institute of Child Health and Human Development