Editors' ChoiceDrug Discovery

Fixing Dendritic Spines in Fragile X

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Science Translational Medicine  10 Apr 2013:
Vol. 5, Issue 180, pp. 180ec60
DOI: 10.1126/scitranslmed.3006266

Studies in humans and animal models have converged on the idea that autism spectrum disorders including fragile X syndrome (FXS) may arise as a consequence of dysfunctional synapses. Fixing aberrant synapses would seem to be an overwhelming challenge; there are 0.15 quadrillion of them in the human cortex. FXS results from transcriptional silencing of the FMR1 gene and loss of the mRNA binding protein FMRP. A mouse in which Fmr1 has been knocked out recapitulates the core pathophysiology of FXS, including increased dendritic spine density, seizures, and hyperactivity. Studies in FXS mice have revealed that FMRP inhibits translation at the synapse in response to metabotropic glutamate receptor signaling. One treatment strategy—reducing mGluR5 signaling—has been shown to reverse pathophysiology in FXS mice and is now in clinical trials. In a new study, Dolan et al. take a different tack in developing a small-molecule inhibitor to reverse the dendritic spine defect in FXS mice.

Previously, this group found that inhibition of p21-activated kinase (PAK), a serine threonine kinase that modulates the actin cytoskeleton, resulted in small, sparse cortical dendritic spines in mice, a phenotype that is opposite of that found in FXS mice, which have an excess of dendritic spines. The investigators then found that when transgenic mice expressing a dominant negative form of PAK were crossed with mice in which Fmr1 had been knocked out, the FXS dendritic spine pathology improved, as did behavioral impairments. Dolan et al. now build on these insights by identifying a small-molecule inhibitor of PAK, FRAX486. When they treated FXS mice with FRAX486, the authors obtained rescue of dendritic spine pathology and amelioration of seizures, hyperactivity, and repetitive behaviors. These encouraging findings suggest a new strategy and drug candidate for the treatment of FXS and potentially other neuropsychiatric disorders involving dendritic spine abnormalities.

B. M. Dolan et al., Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by the small-molecule PAK inhibitor FRAX486. Proc. Natl. Acad. Sci. U.S.A., publiahed online 18 March 2013 (10.1073/pnas.1219383110). [Pubmed]

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