Research points to potential treatment strategy for Fragile X syndrome

With no cure available, Fragile X syndrome is the most common form of inherited intellectual disability. Individuals with the syndrome cannot produce enough of a protein—called the fragile X mental retardation protein (FMRP)—whose function has remained somewhat mysterious. Now researchers, reporting online April 17 in the Cell Press journal Molecular Cell, show that the FMRP protein regulates the machinery within a cell that is responsible for generating all functional proteins. The findings provide new insights into how Fragile X syndrome develops and could lead to novel therapies that might help restore some of the capabilities lost in affected individuals.

FMRP is highly expressed in the brain and is important for normal brain development. Previous studies have shown that FMRP regulates the expression of many proteins throughout the brain, and that in the absence of FMRP, ribosomes—the protein-synthesizing machinery of the cell—will translate some of the brain's genetic material into proteins in an inappropriate fashion, resulting in disease. However, the precise mechanism used by FMRP to regulate protein expression is unknown.

"In this study, we clearly show that FMRP binds directly to the such that it would regulate its function," says Dr. Rajendra Agrawal, one of the senior authors and a principal investigator at the Wadsworth Center, New York State Department of Health and the State University of New York at Albany. "FMRP binds in between the two ribosomal subunits, overlapping with the binding position of various translational factors on the ribosome," he explains. Thus, when FMRP is bound to the ribosome, it influences the binding of other critical factors that attach to the ribosome and are important for the proper production of brain proteins.

The findings were made in , which have FMRP and ribosomes that are similar to those in humans. While the researchers were able to map the primary binding site of FMRP on the ribosome in fruit flies, more detailed studies are needed to help investigators determine if these interactions also occur in humans and identify potential drugs that might target the ribosome to help restore normal production in the brains of patients with Fragile X syndrome.

The findings could also provide insights into other conditions that may be caused by defects in translation of genetic information into proteins. "Similar to FMRP, it is possible that there are other proteins in the cell that bind directly to the ribosome as well to regulate gene expression," says senior author Dr. Simpson Joseph of the University of California at San Diego. "When these translational regulatory proteins are mutated, it may lead to disease."

More information: Molecular Cell, Chen et al.: "Fragile X Mental Retardation Protein Regulates Translation by Binding Directly to the Ribosome." dx.doi.org/10.1016/j.molcel.2014.03.023

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