Fragile X syndrome (FXS) is a prevailing genetic disorder of intellectual disability and autism. There is no efficacious medication for FXS. Through in silico screening with a public database, computational analysis of transcriptome profile in FXS mouse neurons predicts therapeutic value of an FDA-approved drug trifluoperazine. Systemic administration of low-dose trifluoperazine at 0.05 mg/kg attenuates multiple FXS- and autism-related behavioral symptoms. Moreover, computational analysis of transcriptome alteration caused by trifluoperazine suggests a new mechanism of action against PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) activity. Consistently, trifluoperazine suppresses PI3K activity and its down-stream targets Akt (protein kinase B) and S6K1 (S6 kinase 1) in neurons. Further, trifluoperazine normalizes the aberrantly elevated activity of Akt and S6K1 and enhanced protein synthesis in FXS mouse. Together, our data demonstrate a promising value of transcriptome-based computation in identification of therapeutic strategy and repurposing drugs for neurological disorders, and suggest trifluoperazine as a potential treatment for FXS.

脆性 X 综合征 (FXS) 是一种常见的智力障碍和自闭症遗传病。没有针对 FXS 的有效药物。通过使用公共数据库进行计算机筛选，FXS 小鼠神经元转录组谱的计算分析预测了 FDA 批准的药物三氟拉嗪的治疗价值。全身给药 0.05 mg/kg 的低剂量三氟拉嗪可减轻多种 FXS 和自闭症相关的行为症状。此外，由三氟拉嗪引起的转录组改变的计算分析表明了一种针对 PI3K（磷脂酰肌醇-4,5-二磷酸 3-激酶）活性的新作用机制。一贯地，三氟拉嗪抑制神经元中的 PI3K 活性及其下游靶标 Akt（蛋白激酶 B）和 S6K1（S6 激酶 1）。更远，trifluoperazine 使 Akt 和 S6K1 异常升高的活性正常化，并增强 FXS 小鼠的蛋白质合成。总之，我们的数据证明了基于转录组的计算在确定治疗策略和重新利用神经系统疾病的药物方面具有广阔的价值，并建议三氟拉嗪作为 FXS 的潜在治疗方法。