A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice
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ORIGINAL ARTICLE
A Highly Selective MNK Inhibitor Rescues Deficits Associated with Fragile X Syndrome in Mice Tarjani Shukla 1,2 & June Bryan de la Peña 1,2 & John M. Perish 3 & Jonathan E. Ploski 3 & Craig R. Stumpf 4 & Kevin R. Webster 4 & Catherine A. Thorn 3 & Zachary T. Campbell 1,2 Accepted: 12 September 2020 # The American Society for Experimental NeuroTherapeutics, Inc. 2020
Abstract Fragile X syndrome (FXS) is the most common inherited source of intellectual disability in humans. FXS is caused by mutations that trigger epigenetic silencing of the Fmr1 gene. Loss of Fmr1 results in increased activity of the mitogen-activated protein kinase (MAPK) pathway. An important downstream consequence is activation of the mitogen-activated protein kinase interacting protein kinase (MNK). MNK phosphorylates the mRNA cap-binding protein, eukaryotic initiation factor 4E (eIF4E). Excessive phosphorylation of eIF4E has been directly implicated in the cognitive and behavioral deficits associated with FXS. Pharmacological reduction of eIF4E phosphorylation is one potential strategy for FXS treatment. We demonstrate that systemic dosing of a highly specific, orally available MNK inhibitor, eFT508, attenuates numerous deficits associated with loss of Fmr1 in mice. eFT508 resolves a range of phenotypic abnormalities associated with FXS including macroorchidism, aberrant spinogenesis, and alterations in synaptic plasticity. Key behavioral deficits related to anxiety, social interaction, obsessive and repetitive activities, and object recognition are ameliorated by eFT508. Collectively, this work establishes eFT508 as a potential means to reverse deficits associated with FXS. Keywords Fragile X syndrome . FMRP . eFT508 . Behavior . Spinogenesis
eFT508 Attenuates Behavioral Deficits in a Mouse Model of FXS Summary The behavioral deficits associated with fragile X syndrome (FXS) are driven by molecular mechanisms that remain largely unknown. Hyperphosphorylation of eIF4E, a key translation initiation factor, is well studied in the context of fragile X syndrome. Here, we reveal that precise control of protein translation with a small molecule inhibitor, eFT508, can resolve key phenotypes present in FXS. Systemic treatment with a potent MNK inhibitor rescues the core phenotypic deficiencies in FXS. This research provides evidence for a potential therapeutic in the context of FXS. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s13311-020-00932-4) contains supplementary material, which is available to authorized users. * Zachary T. Campbell [email protected] 1
Department of Biological Sciences, University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX 75080, USA
2
Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX 75080, USA
3
School of Behavioral and Brain Sciences, University of Texas at Dallas, Richardson, TX 75080, USA
4
eFFECTOR Therapeutics, San Diego, CA 92121, USA
Introduction Fragile X syndrome (FXS) is the most common
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