New insight into fragile X tremor/ataxia syndrome

Researchers have reported new insight into the pathology underlying a recently identified neurological disorder that strikes middle-aged adults that is caused by alterations in the same gene that causes fragile X syndrome.

Fragile X tremor/ataxia syndrome (FXTAS) overwhelmingly affects males, usually in their 50s, causing Parkinson's-like symptoms and cognitive decline. In contrast, fragile X syndrome manifests itself from birth and is the most common form of X-linked mental retardation.

In two related papers in the August 16, 2007, issue of the journal Neuron, published by Cell Press, researchers report studies revealing how FXTAS might arise from malfunction of the same gene that causes fragile X syndrome.

They theorize that the mutation causing FXTAS likely triggers a failure of the mechanism for transporting the genetic material messenger RNA within neurons to protein-making sites. The result, they theorize, is a lethal clogging of brain cells.

One paper was authored by a research team led by Stephen Warren, and the other by researchers led by co-senior authors David Nelson and Juan Botas.

FXTAS, like fragile X syndrome, is produced by a mutation in the fragile X mental retardation gene, FMR1. However, unlike fragile X syndrome, in which the mutation causes complete loss of the gene's functions, the FXTAS mutation produces a different, more subtle abnormality. Both mutations cause the FMR1 gene to stutter," that is to have abnormally long strings of repeats of the same sequence of three genetic units, called nucleotides. However, while the fragile X mutation produces more than 200 repeats, causing loss of function, 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 the messenger RNA that carries genetic information from the nucleus to the protein-making machinery. A central puzzle has been how the string of stutters in the abnormally long messenger RNA of FXTAS patients produces the neural pathology of the disease, and why it appears late in life.

The research teams both 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 had suggested that the longer string of repeats in the mutant messenger RNA might abnormally bind proteins that normally attach to the RNA as part of the transport process. Such binding would 'sop up' all of the transport protein, crippling transport and clogging the cell with inclusions made of messenger RNA and attached proteins.

Warren and colleagues explored whether one such protein, called Pur , might be involved in the pathological process. Their studies with fruit flies revealed that Pur does specifically attach to the FXTAS repeats and that the protein is a component of the cell-clogging inclusions characteristic of FXTAS pathology. What's more, they found that producing more Pur in the mutant flies suppressed the neural abnormalities in the flies.

The researchers also found inclusions in the brains of human FXTAS patients to contain Pur .

In their Neuron article, Nelson, Botas, and colleagues reported studies using the mutant flies on the role of two other RNA-binding proteins in FXTAS pathology. They found that two proteins called CUGBP1 and hnRNP A2/B1 were involved in the pathology. CUGBP1 attaches itself to hnRNP A2/B1, which in turn attaches to the abnormal repeats in the mutant messenger RNA, they found. What's more, when they 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.

Besides revealing the underlying pathological mechanism of FXTAS, wrote Nelson, Botas, and their colleagues, their findings can also explain differences among people in the severity of the disease. Perhaps, they wrote, different people might produce different levels of the RNA-binding proteins, and higher levels might offer some protection in affected people.