Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Department of Developmental Biology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA; Needleman Center for Neurometabolism and Axonal Therapeutics, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Cell Rep. 2019 Sep 3;28(10):2581-2593.e5. doi: 10.1016/j.celrep.2019.08.001.
Fragile X syndrome (FXS) is the leading heritable cause of intellectual disability and commonly co-occurs with autism spectrum disorder. Silencing of the Fmr1 gene leads to the absence of the protein product, fragile X mental retardation protein (FMRP), which represses translation of many target mRNAs. Excess translation of these targets is one cause of neuronal dysfunction in FXS. Utilizing the Drosophila model of FXS, we identified the mitogen-activated protein kinase kinase kinase (MAP3K) Wallenda/dual leucine zipper kinase (DLK) as a critical target of FMRP. dFMRP binds Wallenda mRNA and is required to limit Wallenda protein levels. In dFmr1 mutants, Wallenda signaling drives defects in synaptic development, neuronal morphology, and behavior. Pharmacological inhibition of Wallenda in larvae suppresses dFmr1 neurodevelopmental phenotypes, while adult administration prevents dFmr1 behavioral defects. We propose that in dFmr1 mutants chronic Wallenda/DLK signaling disrupts nervous system development and function and that inhibition of this kinase cascade might be a candidate therapeutic intervention for the treatment of FXS.
脆性 X 综合征 (FXS) 是遗传性智力障碍的主要病因，通常与自闭症谱系障碍并存。Fmr1 基因的沉默导致缺乏蛋白质产物，脆性 X 智力迟钝蛋白 (FMRP)，它抑制许多靶 mRNA 的翻译。这些靶标的过度翻译是 FXS 中神经元功能障碍的一个原因。利用 FXS 的果蝇模型，我们确定了丝裂原活化蛋白激酶激酶激酶 (MAP3K) Wallenda/双亮氨酸拉链激酶 (DLK) 作为 FMRP 的一个关键靶标。dFMRP 结合 Wallenda mRNA，并限制 Wallenda 蛋白水平。在 dFmr1 突变体中，Wallenda 信号驱动突触发育、神经元形态和行为缺陷。幼虫中 Wallenda 的药理学抑制抑制 dFmr1 的神经发育表型，而成年时给药可防止 dFmr1 的行为缺陷。我们提出，在 dFmr1 突变体中，慢性 Wallenda/DLK 信号破坏神经系统的发育和功能，抑制该激酶级联可能是治疗 FXS 的候选治疗干预措施。
