Three-prime repair exonuclease 1 (TREX1) is an anti-viral enzyme that cleaves nucleic acids in the cytosol, preventing accumulation and a subsequent type I interferon-associated inflammatory response. Autoimmune diseases, including Aicardi-Goutières syndrome (AGS) and systemic lupus erythematosus, can arise when TREX1 function is compromised. AGS is a neuroinflammatory disorder with severe and persistent intellectual and physical problems. Here we generated a human AGS model that recapitulates disease-relevant phenotypes using pluripotent stem cells lacking TREX1. We observed abundant extrachromosomal DNA in TREX1-deficient neural cells, of which endogenous Long Interspersed Element-1 retrotransposons were a major source. TREX1-deficient neurons also exhibited increased apoptosis and formed three-dimensional cortical organoids of reduced size. TREX1-deficient astrocytes further contributed to the observed neurotoxicity through increased type I interferon secretion. In this model, reverse-transcriptase inhibitors rescued the neurotoxicity of AGS neurons and organoids, highlighting their potential utility in therapeutic regimens for AGS and related disorders.

中文翻译：

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使用人类干细胞对 TREX1 依赖性自身免疫疾病进行建模强调了 L1 积累是神经炎症的来源。

三素修复核酸外切酶 1 (TREX1) 是一种抗病毒酶，可切割细胞质中的核酸，防止积累和随后的 I 型干扰素相关炎症反应。当 TREX1 功能受损时，可能会出现自身免疫性疾病，包括 Aicardi-Goutières 综合征 (AGS) 和系统性红斑狼疮。AGS 是一种神经炎症性疾病，具有严重且持续的智力和身体问题。在这里，我们生成了一个人类 AGS 模型，该模型使用缺乏 TREX1 的多能干细胞概括了与疾病相关的表型。我们在 TREX1 缺陷型神经细胞中观察到丰富的染色体外 DNA，其中内源性长散在元素 1 反转录转座子是主要来源。TREX1 缺陷神经元也表现出细胞凋亡增加并形成尺寸减小的三维皮质类器官。TREX1 缺陷型星形胶质细胞通过增加 I 型干扰素分泌进一步导致观察到的神经毒性。在这个模型中，逆转录酶抑制剂挽救了 AGS 神经元和类器官的神经毒性，突出了它们在 AGS 和相关疾病治疗方案中的潜在用途。