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 ribosome 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 fruit flies, 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 protein 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."