Studies from two groups reveal three proteins involved in the pathology of fragile X tremor/ataxia syndrome.

In two related papers in the August 16 issue of Neuron, researchers reveal a possible mechanism of how fragile X tremor/ataxia syndrome (FXTAS) might arise from the gene FMR1, the same gene that causes fragile X syndrome.

Unlike fragile X syndrome in which the mutation causes complete loss of the gene’s functions, the FXTAS variation produces a more subtle abnormality. Both SNPs cause the FMR1 gene to have long strings of repeats of the same sequence of three nucleotides. However, while the fragile X variation produces more than 200 repeats, the FXTAS mutation produces between 55 and 200 repeats versus fewer than 55 repeats for most unaffected people.

These repeats in the mutant DNA gene are copied onto mRNA. Scientists have been uncertain about how the string of stutters in the abnormally long mRNA of FXTAS patients produces the neural pathology of the disease and why it appears late in life.

The research teams studied the disease pathology using a mutant strain of the fruit fly Drosophila altered to have a stuttering form of the gene comparable to the FXTAS mutation in humans. Previous studies have suggested that the longer string of repeats in the mutant mRNA might abnormally bind proteins that usually attach to the RNA as part of the transport process. Such binding would soak up all the transport protein, clogging the cell with inclusions made of mRNA and attached proteins.

A team from Emory University School of Medicine examined whether one such protein, Pur á, might be involved in the pathological process. They found that this protein specifically attaches to the FXTAS repeats and that it is a component of the cell clogging inclusions characteristic of FXTAS pathology. The researchers confirmed that inclusions in the brains of human FXTAS patients contain Pur á.

Additionally, the Emory group observed that producing more Pur á in the mutant flies suppressed the neural abnormalities in the flies.

In the second article by scientists at Baylor College of Medicine, the team examined the role of two other RNA-binding proteins, CUGBP1 and hnRNP A2/B1. They discovered that CUGBP1 attaches itself to hnRNP A2/B1, which in turn attaches to the abnormal repeats in the mutant mRNA. When the scientists engineered dual-mutant flies that in addition to having the abnormal FMR1 gene also overproduced either of the two proteins, they found that the flies showed less neurodegeneration.

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