Several Proteins Tied to Neuronal Defects May Offer Way of Treating FXTAS, Study Suggests

A group of proteins linked with nerve cell defects could represent promising treatment targets for people with fragile X tremor-ataxia syndrome (FXTAS), a study in mice suggested.

The study, “Reduction of Fmr1 mRNA Levels Rescues Pathological Features in Cortical Neurons in a Model of FXTAS,” was published in the journal Molecular Therapy – Nucleic Acids.

FXTAS is a common condition in families affected by fragile X syndrome. It is characterized by movement abnormalities (ataxia) and rhythmic, involuntary movements (tremors) resembling the symptoms of Parkinson’s disease. Anxiety and cognitive decline may also be present.

Unlike fragile X, which appears early in life, FXATS occurs during adulthood and predominantly affects men older than 50.

Both conditions are caused by an unusually large DNA segment in the FMR1 gene. While people with fragile X typically have a “full” mutation with over 200 CGG repeats, those with FXTAS carry a premutation comprising 55–200 such repeats. (Of note, C stands for cytosine and G for guanine, two of the four building blocks of DNA).

FMR1 provides instructions for making the fragile X mental retardation protein, or FMRP. This protein is present in many tissues, but it is believed to play an important role in the functioning of nerve cells, or neurons, and their communication.

Although the genetic cause of FXTAS is well-established, the reason why people with this disorder develop movement and cognition problems associated with nerve cell damage is still unclear.

In addition, although FXTAS has been mostly viewed as a late-onset disorder, certain symptoms in patients as well as learning and memory problems seen in mouse models suggest the disorder may start damaging the body earlier than previously thought, disrupting the development of neurons.

So far, no specific therapy is available for FXTAS. Treatment with brexanolone (or allopregnanolone) improved cognitive functioning in people with this disorder. However, nothing is known for its effects on neurodevelopmental outcomes “opening the possibility to search for new targetable pathways in young patients,” the researchers wrote.

Scientists have characterized three potential culprits at the root of FXTAS — clumps of materials inside nerve cells, the presence of a short and abnormal FMRP protein, and elevated levels of FMR1 messenger RNA (mRNA), derived from DNA in the production of FMRP.

Using a mouse model of FXTAS, the team from France and Germany specifically studied the impact of elevated FMR1 mRNA levels and whether bringing those levels down to normal would be beneficial.

As seen in previous studies, the results showed that neurons in the brains of mice with FXTAS-like disease had several abnormalities — these cells were shorter, were less branched, and had longer dendritic spines (tiny protrusions involved in the communication with other nerve cells).

Importantly, when the researchers genetically engineered neurons to lower the amounts of FMR1 mRNA, they were able to correct these defects.

The scientists identified several proteins altered in neurons of mice with FXTAS. They spotted 29 proteins — including Tia1, Hnrnpll, ROAA, and P5CDH — whose levels returned to normal at the same time the neuronal defects were repaired.

Overall, the researchers believe these proteins could hold the key for the molecular pathways underlying the disease, and may represent “promising pharmacological targetable molecules for early therapeutic intervention for FXTAS,” they wrote.