Department of Biomedicine and Prevention, Faculty of Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Institute of Neurosurgery, Fondazione Policlinico Universitario A. Gemelli Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Catholic University, 00168 Rome, Italy.
Cells. 2023 Feb 27;12(5):758. doi: 10.3390/cells12050758.
Fragile X syndrome (FXS) is the most common form of monogenic intellectual disability and autism, caused by the absence of the functional fragile X messenger ribonucleoprotein 1 (FMRP). FXS features include increased and dysregulated protein synthesis, observed in both murine and human cells. Altered processing of the amyloid precursor protein (APP), consisting of an excess of soluble APPα (sAPPα), may contribute to this molecular phenotype in mice and human fibroblasts. Here we show an age-dependent dysregulation of APP processing in fibroblasts from FXS individuals, human neural precursor cells derived from induced pluripotent stem cells (iPSCs), and forebrain organoids. Moreover, FXS fibroblasts treated with a cell-permeable peptide that decreases the generation of sAPPα show restored levels of protein synthesis. Our findings suggest the possibility of using cell-based permeable peptides as a future therapeutic approach for FXS during a defined developmental window.
脆性 X 综合征（FXS）是最常见的单基因智力障碍和自闭症形式，由功能性脆性 X 信使核糖核蛋白 1（FMRP）缺失引起。FXS 的特征包括蛋白质合成增加和失调，这在鼠类和人类细胞中均有观察到。淀粉样前体蛋白（APP）的异常加工，包括可溶性 APPα（sAPPα）过量，可能导致小鼠和人类成纤维细胞中的这种分子表型。在这里，我们显示了 FXS 个体的成纤维细胞、诱导多能干细胞（iPSC）来源的人类神经前体细胞和前脑类器官中 APP 加工的年龄依赖性失调。此外，用一种可穿透细胞的肽处理 FXS 成纤维细胞可恢复蛋白质合成水平。我们的发现表明，在特定的发育窗口内，使用基于细胞的可穿透肽作为 FXS 的未来治疗方法具有可能性。
