Targeting Translation Control with p70 S6 Kinase I Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice
Targeting Translation Control with p70 S6 Kinase I Inhibitors to Reverse Phenotypes in Fragile X Syndrome Mice
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DOI：
10.1038/npp.2015.369
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发表时间：
2016-07-01
影响因子：
7.6
通讯作者：
Klann, Eric
中科院分区：
文献类型：
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作者：
Bhattacharya, Aditi;Mamcarz, Maggie;Klann, Eric
异常的神经元翻译与许多脑部疾病的病因有关。尽管 mTORCI-p70 核糖体 S6 激酶 I (S6KI) 信号传导对于翻译控制至关重要，但由于缺乏 S6KI 特异性抑制剂，体内药理学操作仅针对“mTORCI”。然而，S6KI 的小分子抑制剂可能会改善基于异常翻译和蛋白质表达的疾病病理表型。其中一种病症是脆性 X 综合征 (FXS)，它被认为是由过度的神经元翻译引起的，并且是自闭症谱系障碍 (ASD) 最常见的遗传原因。迄今为止，FXS 的潜在治疗干预措施主要集中在翻译控制上游的靶标上，以使 FXS 相关表型正常化。在这里，我们测试了两种 S6KI 抑制剂 PF-4708671 和 FS-115 使 FXS 模型小鼠表现出的翻译稳态和其他表型正常化的能力。我们发现，尽管两种 S6K1 抑制剂的药代动力学特征不同，但它们在逆转 FXS 模型小鼠的多种疾病相关表型方面有重叠，包括蛋白质合成过度、不适当的社会行为、行为不灵活、树突棘形态改变和大睾丸发育。相比之下，这两种抑制剂在挽救刻板的大理石埋藏行为和体重增加方面的能力有所不同。这些发现提供了 S6KI 抑制剂在体内对 FXS 影响的初步药理学特征，并对涉及异常 mTORC I-S6KI 信号传导的其他神经精神疾病具有治疗意义。
Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORCI-p70 ribosomal S6 kinase I (S6KI) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively 'mTORCI due to the paucity of specific inhibitors to S6KI. However, small molecule inhibitors of S6KI could potentially ameliorate pathological phenotypes of diseases, which are based on aberrant translation and protein expression. One such condition is fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorder (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6KI inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendntic spine morphology, and macroorchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble-burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6KI inhibitors in vivo for FXS, and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC I-S6KI signaling.