Fragile X syndrome (FXS) is the most frequent form of familial intellectual disability. FXS results from the lack of the RNA-binding protein FMRP and is associated with the deregulation of signaling pathways downstream of mGluRI receptors and upstream of mRNA translation. We previously found that diacylglycerol kinase kappa (DGKk), a main mRNA target of FMRP in cortical neurons and a master regulator of lipid signaling, is downregulated in the absence of FMRP in the brain of Fmr1-KO mouse model. Here we show that adeno-associated viral vector delivery of a modified and FMRP-independent form of DGKk corrects abnormal cerebral diacylglycerol/phosphatidic acid homeostasis and FXS-relevant behavioral phenotypes in the Fmr1-KO mouse. Our data suggest that DGKk is an important factor in FXS pathogenesis and provide preclinical proof of concept that its replacement could be a viable therapeutic strategy in FXS.

中文翻译：

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AAV 传递的二酰基甘油激酶 DGKk 实现了脆性 X 综合征小鼠模型的长期拯救。

脆性 X 综合征 (FXS) 是最常见的家族性智力障碍。FXS 是由于缺乏 RNA 结合蛋白 FMRP 而导致的，并且与 mGluRI 受体下游和 mRNA 翻译上游信号通路的失调有关。我们之前发现二酰基甘油激酶 kappa (DGKk) 是皮质神经元中 FMRP 的主要 mRNA 靶点和脂质信号传导的主要调节剂，在 Fmr1-KO 小鼠模型的大脑中没有 FMRP 的情况下下调。在这里，我们显示腺相关病毒载体递送修饰的和 FMRP 独立形式的 DGKk 可纠正 Fmr1-KO 小鼠中异常的脑二酰基甘油/磷脂酸稳态和 FXS 相关行为表型。