Research ArticleFRAGILE X SYNDROME

Aberrant Rac1-cofilin signaling mediates defects in dendritic spines, synaptic function, and sensory perception in fragile X syndrome

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Sci. Signal.  07 Nov 2017:
Vol. 10, Issue 504, eaan0852
DOI: 10.1126/scisignal.aan0852

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Rac1-PAK signaling a target for FXS therapy?

The inherited intellectual disability and autism-associated disorder fragile X syndrome (FXS) is caused by the loss of the mRNA-binding protein FMRP and characterized by an increased formation, but impaired maturation, of dendritic spines. Spine outgrowth and maturation are dependent on actin polymerization-depolymerization dynamics. Pyronneau et al. found that loss of FMRP in mice increased the abundance and activity of the GTPase Rac1. Rac1 activated the kinases PAK and LIMK1, which inactivated cofilin, thus preventing actin depolymerization dynamics. A pharmacological inhibitor of PAK decreased the number of immature spines and improved sensory processing in FXS model mice, suggesting that targeting this pathway may be therapeutic in patients.