Ataxia-telangiectasia (A-T) is a genetic disorder caused by the lack of functional ATM kinase. A-T is characterized by chronic inflammation, neurodegeneration and premature ageing features that are associated with increased genome instability, nuclear shape alterations, micronuclei accumulation, neuronal defects and premature entry into cellular senescence. The causal relationship between the detrimental inflammatory signature and the neurological deficiencies of A-T remains elusive. Here, we utilize human pluripotent stem cell-derived cortical brain organoids to study A-T neuropathology. Mechanistically, we show that the cGAS-STING pathway is required for the recognition of micronuclei and induction of a senescence-associated secretory phenotype (SASP) in A-T olfactory neurosphere-derived cells and brain organoids. We further demonstrate that cGAS and STING inhibition effectively suppresses self-DNA-triggered SASP expression in A-T brain organoids, inhibits astrocyte senescence and neurodegeneration, and ameliorates A-T brain organoid neuropathology. Our study thus reveals that increased cGAS and STING activity is an important contributor to chronic inflammation and premature senescence in the central nervous system of A-T and constitutes a novel therapeutic target for treating neuropathology in A-T patients.

中文翻译：

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抑制 cGAS-STING 通路可改善共济失调-毛细血管扩张脑类器官的过早衰老特征

共济失调毛细血管扩张症 (AT) 是一种由缺乏功能性 ATM 激酶引起的遗传疾病。AT 的特点是慢性炎症、神经退行性变和过早衰老特征，这些特征与基因组不稳定性增加、核形状改变、微核积累、神经元缺陷和过早进入细胞衰老有关。有害的炎症特征与 AT 的神经缺陷之间的因果关系仍然难以捉摸。在这里，我们利用人类多能干细胞衍生的皮质脑类器官来研究 AT 神经病理学。从机制上讲，我们表明 cGAS-STING 通路是在 AT 嗅觉神经球衍生细胞和脑类器官中识别微核和诱导衰老相关分泌表型 (SASP) 所必需的。我们进一步证明，cGAS 和 STING 抑制可有效抑制 AT 脑类器官中自身 DNA 触发的 SASP 表达，抑制星形胶质细胞衰老和神经变性，并改善 AT 脑类器官神经病理学。因此，我们的研究表明，cGAS 和 STING 活性的增加是导致 AT 中枢神经系统慢性炎症和过早衰老的重要原因，并构成了治疗 AT 患者神经病理学的新治疗靶点。