Department of Science, Roma Tre University, Viale Marconi 446, 00146 Rome, Italy.
Neuroendocrinology Metabolism and Neuropharmacology Unit, IRCSS Fondazione Santa Lucia, Via del Fosso Fiorano 64, 00143 Rome, Italy.
Int J Mol Sci. 2022 Mar 21;23(6):3408. doi: 10.3390/ijms23063408.
Fragile X Syndrome (FXS) is the most frequent form of inherited X-linked pathology, associated with an intellectual and developmental disability, and currently considered the first monogenic cause of autism spectrum disorder (ASD). Low levels of total cholesterol reported in the serum of FXS patients, and evidence that FMRP targets a subset of mRNAs encoding proteins of lipid synthesis and transport suggests that the cholesterol metabolism impairments could be involved in FXS. Thus, the aim of the presented work was to investigate the modulations of the cholesterol biosynthetic pathway and its end-products in a recently developed rat model of FXS. Here, we show that this experimental model mimics what is found in FXS patients, exhibiting a lower serum cholesterol content, accompanied by a reduction in food intake and body weight compared to WT animals. Moreover, alterations of proteins committed to cholesterol synthesis and uptake have been observed in the amygdala, prefrontal cortex and nucleus accumbens. Interestingly, the end-products show a brain region-dependent modulation in rats. Overall, our results demonstrate that the cholesterol biosynthetic pathway is altered in some brain regions of this preclinical model of FXS. This finding has relevance for future studies to delve deeper into the involvement of this metabolic process in FXS, and thus its possible role as a therapeutic target.
脆性 X 综合征 (FXS) 是最常见的遗传性 X 连锁疾病，与智力和发育障碍有关，目前被认为是自闭症谱系障碍 (ASD) 的第一个单基因病因。FXS 患者血清中总胆固醇水平低，并且有证据表明 FMRP 靶向编码脂质合成和转运蛋白的一组 mRNA，这表明胆固醇代谢损伤可能与 FXS 有关。因此，本研究的目的是研究最近开发的 FXS 大鼠模型中胆固醇生物合成途径及其终产物的调节。在这里，我们表明该实验模型模拟了 FXS 患者的情况，表现为血清胆固醇含量降低，与 WT 动物相比，食物摄入量和体重减少。此外，在杏仁核、前额叶皮层和伏隔核中观察到与胆固醇合成和摄取有关的蛋白质发生改变。有趣的是，在大鼠中，终产物表现出脑区依赖性的调节。总之，我们的研究结果表明，在 FXS 的这种临床前模型的一些脑区中，胆固醇生物合成途径发生了改变。这一发现对于未来的研究深入探讨该代谢过程在 FXS 中的作用及其作为治疗靶点的可能性具有重要意义。
