Division of Neuroscience, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom.
Geoffrey Jefferson Brain Research Centre, The Manchester Academic Health Science Centre, Northern Care Alliance National Health Service (NHS) Foundation Trust, The University of Manchester, Manchester, United Kingdom.
Front Immunol. 2023 Mar 6;14:1100967. doi: 10.3389/fimmu.2023.1100967. eCollection 2023.
Aicardi-Goutières syndrome (AGS1-9) is a genetically determined encephalopathy that falls under the type I interferonopathy disease class, characterized by excessive type I interferon (IFN-I) activity, coupled with upregulation of IFN-stimulated genes (ISGs), which can be explained by the vital role these proteins play in self-non-self-discrimination. To date, few mouse models fully replicate the vast clinical phenotypes observed in AGS patients. Therefore, we investigated the use of zebrafish as an alternative species for generating a clinically relevant model of AGS. Using CRISPR-cas9 technology, we generated a stable mutant zebrafish line recapitulating AGS5, which arises from recessive mutations in . The resulting homozygous mutant zebrafish larvae possess a number of neurological phenotypes, exemplified by variable, but increased expression of several ISGs in the head region, a significant increase in brain cell death, microcephaly and locomotion deficits. A link between IFN-I signaling and cholesterol biosynthesis has been highlighted by others, but not previously implicated in the type I interferonopathies. Through assessment of neurovascular integrity and qPCR analysis we identified a significant dysregulation of cholesterol biosynthesis in the zebrafish model. Furthermore, dysregulation of cholesterol biosynthesis gene expression was also observed through RNA sequencing analysis of AGS patient whole blood. From this novel finding, we hypothesize that cholesterol dysregulation may play a role in AGS disease pathophysiology. Further experimentation will lend critical insight into the molecular pathophysiology of AGS and the potential links involving aberrant type I IFN signaling and cholesterol dysregulation.
Aicardi-Goutières 综合征（AGS1-9）是一种遗传性脑病，属于 I 型干扰素病类，其特征是 I 型干扰素（IFN-I）活性过度，伴有 IFN 刺激基因（ISGs）的上调，这可以用这些蛋白质在自我非自我识别中的重要作用来解释。迄今为止，很少有小鼠模型能完全复制 AGS 患者观察到的广泛临床表型。因此，我们研究了利用斑马鱼作为替代物种来产生 AGS 的临床相关模型。我们使用 CRISPR-cas9 技术，生成了一种稳定的突变斑马鱼系，该系模拟 AGS5，这是由 中的隐性突变引起的。由此产生的纯合突变斑马鱼幼虫具有多种神经表型，例如头部几个 ISGs 的表达可变但增加，脑细胞死亡、小头症和运动缺陷显著增加。干扰素-I 信号和胆固醇生物合成之间的联系已被其他人强调，但以前与 I 型干扰素病无关。通过评估神经血管完整性和 qPCR 分析，我们确定了斑马鱼模型中胆固醇生物合成的显著失调。此外，通过对 AGS 患者全血的 RNA 测序分析也观察到胆固醇生物合成基因表达的失调。从这个新发现中，我们假设胆固醇失调可能在 AGS 疾病发病机制中起作用。进一步的实验将为 AGS 的分子发病机制提供关键的见解，并可能涉及异常的 I 型 IFN 信号和胆固醇失调。
