Possible approach discovered for treating fragile X Syndrome

The chromatin binding protein, Brd4, could be a drug target for a common form of inherited intellectual disability, according to a study published in the 17 August 2017 issue of the journal Cell.

The study was carried out by researchers at the Rockefeller University, and C. David Allis and Robert B. Darnell from the university are the co-senior authors of the study.

Fragile X Syndrome (FXS) is a genetic disease that typically causes intellectual disability and specific physical features. Many of the people with FXS experience autism-like symptoms. The disease is estimated to affect about 1 in 2500-4000 males and 1 in 7000-8000 females.

The cause of FXS is a defect in a single gene, FMR1, which is located on the X chromosome. The protein encoded by FMR1 is called FMRP and is critical for normal development of neuronal connections (synapses). FMRP is widely expressed in the body, but is in the highest level in the brain and testes. In FXS, the production of FMRP is not enough, disrupting the formation of synapses and neural circuits and impairing cognitive function.

It has been proposed that FMRP's effect on synaptic plasticity is based on its role in translation regulation. In detail, FMRP has RNA-binding activity, and this allows it to inhibit translation of mRNA. However, mutated FMRP loses the ability to inhibit translation.

The target network of FMRP is complex. Previous studies have identified a group of proteins whose translation is repressed by FMRP. But targeting these proteins has not delivered enough therapeutic benefits.

In this work, Allis, Darnell and colleagues focused on transcriptional regulators that are translationally regulated by FMRP. One of the transcriptional regulators -- Brd4 -- is an epigenetic reader and plays a key role in chromatin remodeling. The researchers found that the negative effects of FMRP loss on chromatin regulation and gene expression could be reversed by inhibiting Brd4. Specifically, inhibition of Brd4 could effectively normalize neuronal synapses and reduce behavioral symptoms.

Taken together, the results suggest that targeting Brd4 presents a therapeutic strategy for FXS.
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