NIH Grant Boosts Research Into Faulty Protein Production in Fragile X

A nearly $2 million grant from the National Institute of Mental Health, part of the National Institutes of Health (NIH),  will help researchers understand the mechanisms underlying impaired protein production in fragile X syndrome.

The awarded project, “Mechanism of Gp1 mGluR-dependent translation and plasticity,” is led by scientists Nien-Pei Tsai and Kai Zhang, at the University of Illinois.

“This proposal brings together two labs with distinct expertise to study Fragile X Syndrome. I am excited that the funding from NIH will make this collaboration happen,” Tsai said in a university press release.

Data from recent clinical trials suggested that experimental fragile X treatments still fall short in terms of efficacy. This lack of efficacy means that the mechanisms underlying the disorder are still elusive.

Fragile X is caused by mutations in the FMR1 gene that disrupt the production of the fragile X mental retardation protein (FMRP), which controls the production of several other proteins at synapses — the place where nerve cells communicate.

Nerve cells need to respond to new information by strengthening or weakening their connections, which is known as synaptic plasticity and is key for learning and memory consolidation. This process requires production of new proteins.

Prior research from Tsai’s lab contributed to understanding the key role of metabotropic glutamate receptors (mGluRs), namely mGluR1, in mediating protein production in nerve cells in a mechanism dependent on the FMRP protein.

Normally, upon activation of mGluR1, the FMRP protein leads to the degradation of another protein known as MDM2, which is known mostly in the field of cancer biology.

Tsai’s work showed that MDM2 is deregulated in mouse models of fragile X, and that it acts as a repressor of protein synthesis via the mGluR. By mediating the breakdown of MDM2, FMRP likely leads to the activation of protein synthesis and elevation of nerve cells’ activity.

Since several small molecules targeting MDM2 have been tested in clinical trials, these prior findings supported their therapeutic potential for restoring protein synthesis in fragile X.

The newly funded project will allow the researchers to broaden the role of MDM2 in neurological disorders such as fragile X.

“We hope our research can ultimately improve the future development of therapies for Fragile X Syndrome,” said Tsai.