Protein Chemistry, Proteomics and Epigenetic Signaling (PPES), Department of Biomedical Sciences, University of Antwerp, 2000 Antwerp, Belgium.
Department of Medical Genetics, University of Antwerp, 2000 Antwerp, Belgium.
Cells. 2022 Apr 13;11(8):1325. doi: 10.3390/cells11081325.
Absence of the Fragile X Messenger Ribonucleoprotein 1 (FMRP) causes autism spectrum disorders and intellectual disability, commonly referred to as the Fragile X syndrome. FMRP is a negative regulator of protein translation and is essential for neuronal development and synapse formation. FMRP is a target for several post-translational modifications (PTMs) such as phosphorylation and methylation, which tightly regulate its cellular functions. Studies have indicated the involvement of FMRP in a multitude of cellular pathways, and an absence of FMRP was shown to affect several neurotransmitter receptors, for example, the GABA receptor and intracellular signaling molecules such as Akt, ERK, mTOR, and GSK3. Interestingly, many of these molecules function as protein kinases or phosphatases and thus are potentially amendable by pharmacological treatment. Several treatments acting on these kinase-phosphatase systems have been shown to be successful in preclinical models; however, they have failed to convincingly show any improvements in clinical trials. In this review, we highlight the different protein kinase and phosphatase studies that have been performed in the Fragile X syndrome. In our opinion, some of the paradoxical study conclusions are potentially due to the lack of insight into integrative kinase signaling networks in the disease. Quantitative proteome analyses have been performed in several models for the FXS to determine global molecular processes in FXS. However, only one phosphoproteomics study has been carried out in knock-out mouse embryonic fibroblasts, and it showed dysfunctional protein kinase and phosphatase signaling hubs in the brain. This suggests that the further use of phosphoproteomics approaches in Fragile X syndrome holds promise for identifying novel targets for kinase inhibitor therapies.
脆性 X 信使核糖核蛋白 1（FMRP）的缺失会导致自闭症谱系障碍和智力障碍，通常被称为脆性 X 综合征。FMRP 是蛋白质翻译的负调节剂，对于神经元发育和突触形成至关重要。FMRP 是几种翻译后修饰（PTMs）的靶标，如磷酸化和甲基化，这些修饰可紧密调节其细胞功能。研究表明，FMRP 参与了多种细胞途径，而 FMRP 的缺失会影响多种神经递质受体，例如 GABA 受体和细胞内信号分子如 Akt、ERK、mTOR 和 GSK3。有趣的是，这些分子中的许多作为蛋白激酶或磷酸酶发挥作用，因此可能可以通过药物治疗进行调节。几项针对这些激酶-磷酸酶系统的治疗方法已在临床前模型中显示出成功，但在临床试验中未能令人信服地显示出任何改善。在这篇综述中，我们强调了在脆性 X 综合征中进行的不同蛋白激酶和磷酸酶研究。我们认为，一些矛盾的研究结论可能是由于缺乏对疾病中整合激酶信号网络的了解所致。已经在 FXS 的几种模型中进行了定量蛋白质组学分析，以确定 FXS 中的全局分子过程。然而，仅在 knock-out 小鼠胚胎成纤维细胞中进行了一项磷酸蛋白质组学研究，该研究显示大脑中的蛋白激酶和磷酸酶信号枢纽功能失调。这表明，进一步在脆性 X 综合征中使用磷酸蛋白质组学方法有望为激酶抑制剂治疗确定新的靶标。
