Department of Biological Sciences, University of Texas at Dallas, 800 W. Campbell Road, Richardson, TX, 75080, USA.
Center for Advanced Pain Studies, University of Texas at Dallas, Richardson, TX, 75080, USA.
Neurotherapeutics. 2021 Jan;18(1):624-639. doi: 10.1007/s13311-020-00932-4. Epub 2020 Oct 1.
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.
脆性 X 综合征（FXS）是人类最常见的遗传性智力障碍病因。FXS 是由导致 Fmr1 基因表观遗传沉默的突变引起的。Fmr1 的缺失导致丝裂原活化蛋白激酶（MAPK）途径的活性增加。一个重要的下游后果是激活丝裂原活化蛋白激酶相互作用激酶（MNK）。MNK 磷酸化真核起始因子 4E（eIF4E）的 mRNA 帽结合蛋白。eIF4E 的过度磷酸化直接与 FXS 相关的认知和行为缺陷有关。降低 eIF4E 磷酸化是 FXS 治疗的一种潜在策略。我们证明，全身性给予高度特异性、可口服的 MNK 抑制剂 eFT508，可减轻小鼠 Fmr1 缺失相关的多种缺陷。eFT508 解决了与 FXS 相关的一系列表型异常，包括巨睾症、异常的 spinogenesis 和突触可塑性改变。与焦虑、社交互动、强迫和重复活动以及物体识别相关的关键行为缺陷通过 eFT508 得到改善。总的来说，这项工作确立了 eFT508 作为一种潜在的方法来逆转与 FXS 相关的缺陷。
