Editors' ChoiceFRAGILE X SYNDROME

Special issue: Fragile X syndrome

See allHide authors and affiliations

Sci. Signal.  07 Nov 2017:
Vol. 10, Issue 504, eaar3825
DOI: 10.1126/scisignal.aar3825

In this issue of Science Signaling, three papers uncover molecular mechanisms of neurological dysfunction in animal models of fragile X syndrome.

Fragile X syndrome (FXS) is an inherited, X-linked intellectual disability disorder caused by a trinucleotide repeat expansion in the gene encoding the RNA-binding protein FMRP. It is a common genetic cause of autism and, like those with autism, patients with FXS exhibit a spectrum of mild to severe learning impairments and neurological dysfunctions. Currently there is no treatment for FXS; however, researchers are beginning to uncover the underlying molecular mechanisms of the disorder. Three papers in this issue of Science Signaling, together with several in the Archives, reveal additional mechanistic insight and new opportunities for therapeutic development.

Pyrroneau et al. showed that inhibiting the Rac1-PAK-LIMK1 signaling pathway reduced the density of immature spines and restored synaptic function and sensory processing in a mouse model of FXS. Loss of FMRP increased the activation of GTPase Rac1, which activated the kinase PAK and subsequently the kinase LIMK1. LIMK1 phosphorylated and inactivated cofilin, which impaired actin depolymerization dynamics that are essential for dendritic spine maturation. In the Archives, Kashima et al. (2016) also found that the LIMK1-cofilin axis is enhanced in FXS-associated neurons (in both animal models and patients). The activation of LIMK1 in the FXS models was caused by the increased abundance and activity of the BMP type II receptor (BMPR2), whose transcript was repressed by FMRP. Inhibiting LIMK1 reduced the density of immature spines and restored synaptic function in animal models (see also Broihier). It would be interesting to explore whether these findings are linked—is BMPR2 the link between FMRP loss and Rac1 activation?—or rather if the mechanisms independently converge on LIMK1.

Also in this issue, Santini et al. showed that reducing eIF4E-mediated, cap-dependent protein translation restored spine development and synaptic function in a mouse model of FXS. They also observed an increase in Rac1 signaling (and consequentially impaired actin dynamics) upon loss of FMRP, which was mediated by an increased interaction between Rac1 and the scaffolding protein CYFIP1. CYFIP1 shuttles between FMRP and Rac1 complexes. When FMRP is present, its occupation of CYFIP1 tempers Rac1-cofilin signaling and enables FMRP’s sequestration of the translation initiating factor eIF4E, hence facilitating actin dynamics and repressing protein synthesis. Protein synthesis is abnormally increased in FXS. A compound that inhibits the interaction between eIF4E and a partner protein, eIF4G, reduced protein synthesis and decreased the CYFIP1-Rac1 interaction, restoring actin dynamics and synaptic function. However, developing a strategy that inhibits protein synthesis would require some care to find the right dosage—or perhaps timing—effects. In the Archives, Tudor et al. showed that protein synthesis specifically in the hippocampus while we sleep is critical for memory formation, consolidation, and learning. That mechanism of protein synthesis was mediated by the kinase complex mTORC1, which increased the activity of eIF4E by sequestering its inhibitor 4EBP2. Thus, as with most cell signaling pathways, finding the right balance is key to attaining proper cell function.

Last, Dear et al. investigated why the basal secretion of matrix metalloproteinases is increased in FXS using a fly model. The abundance of Drosophila Mmp1 was selectively increased in neurons, as was the glypican Dlp1. Dlp1 recruited Mmp1 to the cell surface through a direct interaction between the proteins, facilitating its secretion. The basal increases in Dlp1 and Mmp1 prevented activity-induced synaptogenesis in the flies. Although the mechanism amongst human MMPs and glypicans in this context remains to be investigated, the study suggests that reducing the abundance of MMP might restore synaptic function and that this might be accomplished by targeting a cell surface glypican. Together, these studies provide a substantial number of potentially new therapeutic targets to explore. The high-throughput in vivo FXS drug screen developed by Kashima et al. (2017), which showed that fly larvae locomotion is a reliable readout of the neurological FXS phenotypes, may be of particular use toward this endeavor.

Highlighted Articles

View Abstract

Navigate This Article