Beneath the Surface of Fragile X Syndrome: Study Sheds Light on What’s Happening in Nerve Cells

February 16, 2021 – FRAXA Investigator Dr. Lynne Maquat has just won the Wolf Prize in Medicine for discoveries in RNA biology that helped to enable development of the Moderna and Pfizer vaccines. Her work on Fragile X has uncovered changes in RNA metabolism in this disorder.

“This FRAXA-funded project has turned up some surprising results. At first, it might seem Kurosaki and Maquat have found yet another cellular process which is malfunctioning in Fragile X. But this finding is intimately related to previous findings of abnormal protein synthesis and misregulated transcription in Fragile X.

FMRP (the protein lacking in Fragile X syndrome) is involved in chaperoning messenger RNAs within cells to active sites, and in controlling their translation into many different proteins. Some of these proteins are transcription factors, which feed back to the nucleus to control gene expression. Others are splicing factors, which control how messenger RNAs are edited after production. Still others are involved in this “quality control” process called NMD. However, these are all just different facets of the complex process that cells use to turn the genetic code into the protein building blocks of life. 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. This new research will help guide us in choosing the optimal treatments to restore proper function to Fragile X cells.”

Michael Tranfaglia, MD
Medical Director and Co-Founder

Republished with permission from University of Rochester Medical Center, written by Emily Boynton.

A new study shows that many abnormalities in Fragile X syndrome cells are related to glitches with one of the body’s major quality control systems. Published in Nature Cell Biology, the research provides fresh insight into the molecular mechanisms of the disorder and a pathway to search for potential treatments.

Fragile X syndrome occurs when individuals don’t make the Fragile X protein known as FMRP, which is needed for normal brain development. Currently, little is known about how the loss of this crucial protein leads to the intellectual disability and severe learning problems characteristic of the disease.

Rochester researchers found that many irregularities in cells that lack FMRP are due to misregulated nonsense-mediated mRNA decay, or NMD. Discovered by RNA biologist Lynne E Maquat, PhD, NMD is like a molecular guide that helps our cells make smart decisions that (in most cases) improve cellular function and contribute to good health. For example, NMD helps our cells adjust to changes in development and in their environment, and more rapidly respond to certain stimuli.

Through a series of cellular analyses, Maquat’s team discovered that NMD influences a wide range of genes throughout the brain, including genes that govern motor control and cognitive processes related to attention, learning and language. They also found that when FMRP is absent from cells, as it is in people with Fragile X syndrome, nonsense-mediated mRNA decay shifts into overdrive.

Lynne E Maquat, PhD

Tatsuaki Kurosaki, PhD

In multiple experiments using induced pluripotent stem cells (iPSC) from individuals with Fragile X syndrome, first author and research assistant professor Tatsuaki Kurosaki, PhD revealed that tamping down NMD with compounds called small molecule inhibitors restored some of these neurological functions in cells.

“This is a big step forward in understanding how this disease develops,” said Maquat, senior study author and the J Lowell Orbison Endowed Chair and Professor in the department of Biochemistry and Biophysics at the University of Rochester School of Medicine and Dentistry. “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. It is bad to have no NMD, but is also detrimental to have too much.”

Treatments for Fragile X syndrome can ameliorate symptoms, such as behavior problems, and support services can help build important skills like talking and walking, but there is no cure for the disorder.

Studies in cells provide only a snapshot of the course of a disease. Kurosaki and Maquat are currently using a mouse model of fragile X syndrome to better understand the interplay between FMRP and nonsense-mediated mRNA decay throughout the various stages of development – in utero, post-birth and into adulthood. They hope to learn when and how much NMD is elevated, and subsequently test different compounds to restore it back to normal levels.

Maquat, also the director of the University of Rochester’s Center for RNA Biology, has spent more than 40 years working to understand nonsense-mediated mRNA decay. Central to the NMD process is mRNA or messenger RNA, which takes genetic instructions from DNA and ferries it to another part of the cell where the instructions are translated into proteins. mRNA is a crucial component of gene expression, and Maquat was one of the first scientists to uncover it’s importance in human health and disease and recognize the vast potential of RNA-based treatments.

RNA catapulted into the spotlight in 2020 with the development and approval of multiple mRNA COVID-19 vaccines. Maquat believes this is the tip of the iceberg in the development of RNA-based therapeutics; she sees immense opportunity for the discovery and development of more treatments for infectious diseases, genetic disorders like Fragile X syndrome and myotonic dystrophy, and more.

The research on Fragile X syndrome was supported by the National Institute for General Medical Sciences at the National Institutes of Health, the FRAXA Research Foundation and University of Rochester School of Medicine and Dentistry Pilot Funding in Stem Cell and Regenerative Medicine. In addition to Maquat and Kurosaki, Christoph Proschel, PhD, associate professor in the department of Biomedical Genetics at Rochester, and scientists from the University of Tokyo contributed to the research.

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FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.

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Global Leader in Fragile X Research

FRAXA-funded researchers around the world are leading the way towards effective treatments and ultimately a cure.

Explore Current Research Grants
Help Fund the Cure

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