Wu Yue-Ying, Yang Cui, Yan Hua-Juan, Lu Ping, Zhang Li, Feng Weng-Cai, Long Yue-Sheng
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
Department of Neurology, Institute of Neuroscience, Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and the Ministry of Education of China, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, China.
J Proteomics. 2022 Oct 30;269:104720. doi: 10.1016/j.jprot.2022.104720. Epub 2022 Sep 9.
Loss of fragile X retardation protein (FMRP) leads to fragile X syndrome (FXS), a common cause of inherited intellectual disability. Protein lysine acetylation (K-ac), a reversible post-translational modification of proteins, is associated with the regulation of brain development and neuropathies. However, a comprehensive hippocampal K-ac protein profile in response to FMRP deficiency has not been reported until now. Using LC-MS/MS to analyze the enriched K-ac peptides, this study identified 1629 K-ac hits across 717 proteins in the mouse hippocampus, and these proteins were enriched in several metabolic processes. Of them, 51 K-ac hits across 45 proteins were significantly changed upon loss of FMRP. These altered K-ac proteins were enriched in energy metabolic processes including carboxylic acid metabolism process, aerobic respiration and citrate cycle, linking with several neurological disorders such as lactic acidosis, Lewy body disease, Leigh disease and encephalopathies. In the mouse hippocampus and the hippocampal HT-22 cells, FMRP deficiency could induce altered K-ac modification of several key enzymes, decrease in ATP and increase in lactate. Thus, this study identified a global hippocampal lysine acetylome and an altered K-ac protein profile upon loss of FMRP linked to abnormal energy metabolism, implicating in the pathogenesis of FXS. SIGNIFICANCE: Fragile X syndrome (FXS) is a common inherited neurodevelopment disorder characterized by intellectual disability and an increased risk for autism spectrum disorder. FXS is resulted from silencing of the FMR1 gene, which induces loss of its encoding protein FMRP. Molecular and metabolic changes of Fmr1-null animal models of FXS have been identified to potentially contribute to the pathogenesis of FXS. Here, we used a TMT-labeled quantitative proteomic analysis of the peptides enriched by anti-K-ac antibodies and identified a global K-ac protein profile in the mouse hippocampus with a total of 1629 K-ac peptides on 717 proteins. Of them, 51 K-ac peptides regarding 45 proteins altered in response to loss of FMRP, which were enriched in energy metabolic processes and were implicated in several neurological disorders. Thus this study for the first time provides a global hippocampal lysine acetylome upon FMRP deficiency linked to abnormal metabolic pathways, which may contribute to pathogenic mechanism of FXS.
脆性X智力低下蛋白（FMRP）的缺失会导致脆性X综合征（FXS），这是遗传性智力残疾的常见原因。蛋白质赖氨酸乙酰化（K-乙酰化）是一种蛋白质的可逆翻译后修饰，与大脑发育和神经病变的调节有关。然而，迄今为止，尚未有关于FMRP缺乏时海马体K-乙酰化蛋白质全面概况的报道。本研究使用液相色谱-串联质谱法（LC-MS/MS）分析富集的K-乙酰化肽段，在小鼠海马体中鉴定出717种蛋白质上的1629个K-乙酰化位点，这些蛋白质在多个代谢过程中富集。其中，45种蛋白质上的51个K-乙酰化位点在FMRP缺失时发生了显著变化。这些发生改变的K-乙酰化蛋白质在能量代谢过程中富集，包括羧酸代谢过程、有氧呼吸和柠檬酸循环，与乳酸酸中毒、路易体病、 Leigh病和脑病等多种神经疾病相关。在小鼠海马体和海马体HT-22细胞中，FMRP缺乏可诱导几种关键酶的K-乙酰化修饰改变、ATP减少和乳酸增加。因此，本研究确定了一个整体的海马体赖氨酸乙酰化组以及FMRP缺失时与异常能量代谢相关的K-乙酰化蛋白质谱改变，这与FXS的发病机制有关。意义：脆性X综合征（FXS）是一种常见的遗传性神经发育障碍，其特征为智力残疾和自闭症谱系障碍风险增加。FXS是由FMR1基因沉默导致的，该基因沉默会使其编码的蛋白质FMRP缺失。已确定FXS的Fmr1基因敲除动物模型的分子和代谢变化可能与FXS的发病机制有关。在此，我们使用抗K-乙酰化抗体富集肽段的TMT标记定量蛋白质组学分析，在小鼠海马体中确定了一个整体的K-乙酰化蛋白质谱，共有717种蛋白质上的1629个K-乙酰化肽段。其中，45种蛋白质上的51个K-乙酰化肽段因FMRP缺失而发生改变，这些肽段在能量代谢过程中富集，并与多种神经疾病有关。因此，本研究首次提供了FMRP缺乏时与异常代谢途径相关的整体海马体赖氨酸乙酰化组，这可能有助于FXS的致病机制研究。
