Department of Biochemistry and Functional Genomic, Faculty of Medicine and Health Sciences, Université de Sherbrooke and Centre de Recherche du CHUS, CIUSSS de l'Estrie-CHUS, Sherbrooke, Quebec, Canada.
PLoS One. 2021 May 11;16(5):e0251367. doi: 10.1371/journal.pone.0251367. eCollection 2021.
Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability and is caused by the loss of expression of the Fragile X mental retardation protein (FMRP). In animal model of FXS, the absence of FMRP leads to an aberrant rate of neuronal protein synthesis, which in turn is believed to be at the origin of defects regarding spine morphology and synaptic plasticity. Normalisation of protein synthesis in these models has been associated with a rescue of FXS behavioral and biochemicals phenotype, thus establishing the rate of protein synthesis as one of the most promising monitoring biomarker for FXS. However, rate of protein synthesis alteration in fragile X individuals is not well characterized.
We applied a robust radiolabeled assay to measure rate of protein synthesis in freshly extracted peripheral blood mononuclear cells (PBMCs) and blood platelets. We ultimately settle on PBMCs to measure and compare rate of protein synthesis in 13 males with fragile X and 14 matched controls individuals.
Using this method, we measured a 26.9% decrease (p = 0,0193) in the rate of protein synthesis in fragile X individuals PBMCs. Furthermore, the rate of protein synthesis measurements obtained were highly reproducible, highlighting the robustness of the method.
Our work presents the first evidence of a diminution of the rate of protein synthesis in a human peripheral model of fragile X. Our results also support the finding of previous studies using brain PET imaging in Fragile X individuals. Since our assay only requires a simple venous puncture, it could be used in other cases of intellectual disability in order to determine if an aberrant rate of protein synthesis is a common general mechanism leading to impairment in synaptic plasticity and to intellectual disability.
脆性 X 综合征（FXS）是智力残疾的主要遗传性病因，由脆性 X 智力低下蛋白（FMRP）表达缺失引起。在 FXS 的动物模型中，FMRP 的缺失导致神经元蛋白合成率异常，这反过来被认为是导致脊柱形态和突触可塑性缺陷的原因。这些模型中蛋白质合成的正常化与 FXS 行为和生物化学表型的恢复有关，因此将蛋白质合成率确立为 FXS 最有前途的监测生物标志物之一。然而，脆性 X 个体中蛋白质合成率的改变尚未得到很好的描述。
我们应用一种稳健的放射性标记测定法来测量新提取的外周血单核细胞（PBMCs）和血小板中的蛋白质合成率。我们最终选择 PBMCs 来测量和比较 13 名脆性 X 男性和 14 名匹配对照个体的蛋白质合成率。
使用这种方法，我们测量到脆性 X 个体 PBMCs 中的蛋白质合成率降低了 26.9%（p=0.0193）。此外，蛋白质合成率的测量结果高度重现，突出了该方法的稳健性。
我们的工作首次提供了在脆性 X 人类外周模型中蛋白质合成率降低的证据。我们的结果还支持了先前使用大脑 PET 成像在脆性 X 个体中发现的研究结果。由于我们的测定法仅需要简单的静脉穿刺，因此它可以用于其他智力残疾病例中，以确定异常的蛋白质合成率是否是导致突触可塑性和智力残疾的常见一般机制。
