ATM is a kinase involved in DNA damage response (DDR), regulation of response to oxidative stress, autophagy and mitophagy. Mutations in the ATM gene in humans result in ataxi A–Telangiectasia disease (A–T) characterized by a variety of symptoms with neurodegeneration and premature ageing among them. Since brain is one of the most affected organs in A–T, we have focused on senescence of neural progenitor cells (NPCs) derived from A–T reprogrammed fibroblasts. Accordingly, A–T NPCs obtained through neural differentiation of iPSCs in 5% oxygen possessed some features of senescence including increased activity of SA-β-gal and secretion of IL6 and IL8 in comparison to control NPCs. This phenotype of A–T NPC was accompanied by elevated oxidative stress. A–T NPCs exhibited symptoms of impaired autophagy and mitophagy with lack of response to chloroquine treatment. Additional sources of oxidative stress like increased oxygen concentration (20 %) and H₂O₂ respectively aggravated the phenotype of senescence and additionally disturbed the process of mitophagy. In both cases only A–T NPCs reacted to the treatment. We conclude that oxidative stress may be responsible for the phenotype of senescence and impairment of autophagy in A–T NPCs. Our results point to senescent A–T cells as a potential therapeutic target in this disease.

ATM 是一种参与 DNA 损伤反应 (DDR)、氧化应激反应调节、自噬和线粒体自噬的激酶。人类 ATM 基因的突变导致共济失调 A-毛细血管扩张症 (A-T)，其特征是多种症状，其中包括神经变性和过早衰老。由于大脑是 A-T 中受影响最严重的器官之一，我们专注于源自 A-T 重编程成纤维细胞的神经祖细胞 (NPC) 的衰老。因此，与对照 NPC 相比，通过 iPSC 在 5% 氧气中的神经分化获得的 A-T NPC 具有一些衰老特征，包括 SA-β-gal 的活性增加以及 IL6 和 IL8 的分泌。这种 A-T NPC 表型伴随着氧化应激升高。A-T NPC 表现出自噬和线粒体自噬受损的症状，对氯喹治疗缺乏反应。氧化应激的其他来源，如增加的氧气浓度 (20 %) 和 H₂ O ₂分别加重了衰老表型，并干扰了线粒体自噬过程。在这两种情况下，只有 A-T NPC 对治疗有反应。我们得出结论，氧化应激可能是 A-T NPC 衰老表型和自噬受损的原因。我们的结果表明衰老的 A-T 细胞是这种疾病的潜在治疗靶点。