Clues to Treating Fragile X Come From Altered Gene Regulation Process

Alterations in a genetic quality control mechanism due to loss of FMRP — fully known as fragile X mental retardation protein — may provide clues as to how healthy function might be restored to cells affected by fragile X syndrome.

The study detailing this finding, “Loss of the fragile X syndrome protein FMRP results in misregulation of nonsense-mediated mRNA decay,” was published in the journal Nature Cell Biology.

Although the loss of FMRP underlies fragile X syndrome, exactly how that loss leads to the genetic disorder remains a mystery.

To learn more, researchers from the University of Rochester School of Medicine and Dentistry, in New York, now examined how the deficiency in FMRP affected a cellular process called nonsense-mediated mRNA decay (NMD).

Cells use NMD as a form of genetic quality control. It provides a way to prevent the production of potentially damaging proteins from messenger RNA (mRNA) molecules. NMD also allows cells to fine-tune gene activity in order to flexibly adjust to changes in the environment and responses to stimuli.

Following up on pioneering studies into the role of NMD, the scientists found that this process is central to regulating genes that govern motor control and cognitive processes associated with attention, learning, and language — all of which are typically affected in people with fragile X.

The investigators discovered that, without FMRP present, NMD kicked into overdrive in cells. mRNA molecules normally held in check became unblocked, leading to over-production of their associated proteins.

“While NMD supports our cells in various ways, too much of it can upset a complex molecular balance that sustains the expression of genes and the creation of proteins,” Lynne Maquat, PhD, the study’s senior author and chair and professor in the department of biochemistry and biophysics at UR Medicine, said in a university press release.

Maquat is credited as the RNA biologist who discovered NMD.

“It is bad to have no NMD, but is also detrimental to have too much,” Maquat said.

Using induced pluripotent stem cells (iPSCs) from individuals with fragile X, the researchers found, however, that they could restore some of the cells’ neurological functions. The team did this by using certain small molecules capable of limiting NMD.

Of note, iPSCs can develop into any type of human cell and are derived from skin or blood cells that have been reprogrammed back into an embryonic-like state.

“Our mechanistic studies reveal that many molecular abnormalities in FMRP-deficient cells are attributable—either directly or indirectly—to misregulated NMD,” the investigators wrote.

The team now is seeking to understand the relationship between NMD and fragile X syndrome throughout development, using a mouse model of the disorder. The goal is to learn how much NMD overdrive occurs in various stages of life, all the way from in utero, or in the womb before birth, through adulthood. Certain compounds will be tested to see whether they can restore NMD to healthy levels at these stages.

NMD is not the only process affected by FMRP. Past research has identified roles for the protein in chaperoning mRNA to specific sites within cells, where translation from mRNA to protein occurs. Some of these proteins regulate gene activity, while others play a role in mRNA editing.

At first glance, it may appear that adding NMD to the mix further complicates the picture of how fragile X syndrome arises. But Michael Tranfaglia, MD, the medical director and co-founder of the Fragile X Research Foundation (FRAXA), which partly funded this project, sees this discovery more as a unification of past findings.

The diverse roles played by FMRP targets “are all just different facets of the complex process that cells use to turn the genetic code into the protein building blocks of life,” Tranfaglia said in an email reply.

“The changes caused by the Fragile X mutation are relatively subtle, and potentially reversible, and the targets for fixing NMD may be quite similar to some of the other drug targets we have already identified,” Tranfaglia said. “This new research will help guide us in choosing the optimal treatments to restore proper function to Fragile X cells.”