Modification of DNA-binding Protein May Be New Therapeutic Target for Fragile X, Mouse Study Suggests

Chemical modification of a DNA-binding protein may provide a new therapeutic target to treat fragile X syndrome (FXS), a mouse study suggests.

The study, “Reducing histone acetylation rescues cognitive deficits in a mouse model of Fragile X syndrome,” was published in Nature Communications.

Fragile X syndrome, the most common cause of autism and inherited intellectual disability, is caused by the loss of a protein called FMRP. This protein helps regulate the production of other proteins and plays a role in the development of synapses — specialized connections between nerve cells essential for transmitting nerve impulses.

Although researchers know that FMRP is essential for learning and memory, the reason why its loss results in cognitive disabilities in patients that persist throughout adulthood is not fully understood.

A number of therapeutic targets have been proposed based on the roles of FMRP, discovered mostly by studying the developing and young adult brain. However, such candidates have failed to deliver any effective treatment so far.

While investigating the consequences of FMRP loss in the brains of adult mouse models of fragile X, researchers at the Waisman Center in Wisconsin observed that losing this protein led to an increase in a chemical modification process called acetylation. 

This type of modification is added to specialized DNA-binding proteins called histones and commands which genes are turned “on” and actively expressed (resulting in protein production) or turned “off” and silent.

In particular, a specific cell niche in the brain was altered, containing neural stem cells, which are self-renewing cells that generate neurons and other brain cells during embryonic development and adult life. Altered neural stem cells were located in the hippocampus, a region of the brain involved in the formation of new memories and associated with learning and emotions.

In the brains of fragile X mice, neural stem cells produced higher levels of an enzyme that promotes acetylation and less of another enzyme with the opposite effect. Consequently, this led to an imbalance in acetylation in these cells.

The elevated histone acetylation seen in fragile X mice resulted in an age-related reduction of neural stem cells, which was associated with the cognitive impairments of the disease.

The team was able to reverse the neurological defects by treating mice with two specific chemicals, curcumin and C646, that rebalance acetylation levels; neural stem cells were able to generate new neurons, and learning and behavioral deficits were recovered.

Of note, curcumin, a natural product and food color, has been extensively evaluated for its therapeutic potential in human cancers and neurodegenerative diseases, and is currently being investigated in several clinical trials, including for Alzheimer’s disease.

“Our studies characterize an important role of FMRP in cognitive maintenance in mid-age mature adults through preserving adult [neuron stem cells] pools, which has not been shown before,” the researchers wrote.

“These exciting results represent a novel treatment strategy for FXS, especially for mature adult individuals,” they conclude.