Fradejas-Villar Noelia, Zhao Wenchao, Reuter Uschi, Doengi Michael, Ingold Irina, Bohleber Simon, Conrad Marcus, Schweizer Ulrich
Institut für Biochemie und Molekularbiologie, Universitätsklinikum Bonn, Bonn, Germany.
Institut für Physiologie, Universitätsklinikum Bonn, Bonn, Germany.
Redox Biol. 2021 Nov 12;48:102188. doi: 10.1016/j.redox.2021.102188.
Selenoproteins are a small family of proteins containing the trace element selenium in form of the rare amino acid selenocysteine (Sec), which is decoded by the UGA codon. In humans, a number of pathogenic variants in genes encoding distinct selenoproteins or selenoprotein biosynthesis factors have been identified. Pathogenic variants in selenocysteine synthase (SEPSECS), which catalyzes the last step in Sec-tRNA biosynthesis, were reported in children suffering from progressive cerebello-cerebral atrophy. To understand the pathomechanism associated with SEPSECS deficiency, we generated a novel mouse model recapitulating the respective human pathogenic p.Y334C variant in the murine Sepsecs gene (Sepsecs). Unlike in patients, pups homozygous for the p.Y334C variant died perinatally with signs of cardio-respiratory failure. Perinatal death is reminiscent of the Sedaghatian spondylometaphyseal dysplasia disorder in humans, which is caused by pathogenic variants in the gene encoding the selenoprotein and key ferroptosis regulator glutathione peroxidase 4 (GPX4). Protein expression levels of distinct selenoproteins in Sepsecs mice were found to be generally reduced in brain and isolated cortical neurons, while transcriptomics analysis uncovered an upregulation of NRF2-regulated genes. Crossbreeding of Sepsecs mice with mice harboring a targeted mutation of the catalytically active Sec to Cys in GPX4 rescued perinatal death of Sepsecs mice, showing that the cardio-respiratory defects of Sepsecs mice were caused by the lack of GPX4. Like in Sepsecs mice, selenoprotein expression levels remained low and NRF2-regulated genes remained highly expressed in these compound mutant mice, indicating that selenium-independent GPX4, along with a sustained antioxidant response are sufficient to compensate for dysfunctional Sec-tRNA biosynthesis. Our findings imply that children with pathogenic variants in SEPSECS or GPX4 may even benefit from treatments that incompletely compensate for impaired GPX4 activity.
硒蛋白是一个小家族的蛋白质，它们以稀有氨基酸硒代半胱氨酸（Sec）的形式含有微量元素硒，Sec由UGA密码子解码。在人类中，已经鉴定出编码不同硒蛋白或硒蛋白生物合成因子的基因中的许多致病变体。在患有进行性小脑-脑萎缩的儿童中报道了硒代半胱氨酸合酶（SEPSECS）的致病变体，SEPSECS催化Sec-tRNA生物合成的最后一步。为了了解与SEPSECS缺乏相关的发病机制，我们生成了一种新型小鼠模型，该模型重现了小鼠Sepsecs基因（Sepsecs）中相应的人类致病p.Y334C变体。与患者不同，p.Y334C变体纯合的幼崽在围产期死亡，伴有心肺功能衰竭的迹象。围产期死亡让人联想到人类的Sedaghatian脊柱干骺端发育异常疾病，该疾病由编码硒蛋白和关键铁死亡调节因子谷胱甘肽过氧化物酶4（GPX4）的基因中的致病变体引起。发现Sepsecs小鼠中不同硒蛋白的蛋白质表达水平在大脑和分离的皮质神经元中普遍降低，而转录组学分析发现NRF2调节基因上调。将Sepsecs小鼠与在GPX4中具有催化活性的Sec到Cys靶向突变的小鼠杂交，挽救了Sepsecs小鼠的围产期死亡，表明Sepsecs小鼠的心肺缺陷是由缺乏GPX4引起的。与Sepsecs小鼠一样，这些复合突变小鼠中的硒蛋白表达水平仍然很低，NRF2调节基因仍然高度表达，这表明不依赖硒的GPX4以及持续的抗氧化反应足以补偿功能失调的Sec-tRNA生物合成。我们的研究结果表明，SEPSECS或GPX4中存在致病变体的儿童甚至可能受益于不完全补偿受损GPX4活性的治疗方法。
