Role of Excessive Protein Synthesis in the Ontogeny of FXS

With a $90,000 grant from the FRAXA Research Foundation, Dr. Mark Bear and Dr. Miquel Bosch tested the simple hypothesis that the excessive rate of protein synthesis is not a consequence but the primary cause of the structural alterations occurring in FXS.

$90,000 Grant
Mark Bear, PhD
Principal Investigator
Miquel Bosch, PhD

Miquel Bosch, PhD
Postdoctural Fellow

Massachusetts Institute of Technology (MIT)
2010-2011 FRAXA Research Grant
$90,000 over 2 Years

The shape and structure of neurons is abnormal in fragile X syndrome (FXS). Patients and mouse models of this disease show an excessive number of long, spindly dendritic spines. These structural changes may lead to the hyper-connectivity of neuronal networks that eventually generate cognitive deficits. The genetic defect in FXS results in the loss of the protein FMRP, which acts as a repressor of mRNA translation. Thus, lack of FMRP produces an excessive synthesis of other proteins. Activation of mGluR5 also stimulates protein synthesis and this has led to the theory that exaggerated consequences of mGluR signaling give rise to the symptoms in FXS.

This hypothesis has been supported by data in mice and flies showing that the inactivation of mGluR rescues many manifestations of FXS. However, we do not know whether this effect is specific for the mGluR signaling pathway or a consequence of reducing the overall rate of synthesis of proteins. An exaggerated protein synthesis might directly alter the plastic properties of the synapses and create the superabundance of dendritic spines.

But there has yet to be a direct test of this idea. Here we want to test the simple hypothesis that the excessive rate of protein synthesis is not a consequence but the primary cause of the structural alterations occurring in FXS. We propose to boost the synthesis of proteins by over-expressing eIF4E, a core member of the translation machinery, and analyze whether the development of spines in those neurons show the same phenotype observed in FXS. This knowledge has important therapeutic implications, because there are multiple strategies that can be contemplated to reduce general protein synthesis in the brain.

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