Research ArticleFragile X Syndrome

Selective inhibition of glycogen synthase kinase 3α corrects pathophysiology in a mouse model of fragile X syndrome

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Science Translational Medicine  20 May 2020:
Vol. 12, Issue 544, eaam8572
DOI: 10.1126/scitranslmed.aam8572

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Blocking GSK3α in a fragile X mouse model

Fragile X syndrome is a heritable cause of autism and intellectual disability. Inhibitors of glycogen synthase kinase 3 (GSK3), including lithium, have shown promise in correcting disease phenotypes in a mouse model of fragile X syndrome, but various toxicities have precluded further development of these compounds. McCamphill et al. now report that a major toxicity of GSK3 inhibition, stabilization of β-catenin, could be avoided by selective pharmacological inhibition of the α paralog of GSK3. Furthermore, the authors found that selective inhibition of GSK3α was sufficient to correct a range of disease phenotypes in a mouse model of fragile X syndrome, whereas inhibition of GSK3β was ineffective.

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