JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.
JUN upregulation drives aberrant transposable element mobilization, associated innate immune response, and impaired neurogenesis in Alzheimer's disease.
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DOI：
10.1038/s41467-023-43728-8
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发表时间：
2023-12-04
影响因子：
16.6
通讯作者：
Trizzino, Marco
中科院分区：
文献类型：
--
作者：
Scopa, Chiara;Barnada, Samantha M.;Cicardi, Maria E.;Singer, Mo;Trotti, Davide;Trizzino, Marco
成人神经源性衰退、炎症和神经变性是阿尔茨海默病（AD）的表型标志。最近报道了AD异染色质区转座因子（TE）的移动，但其潜在机制仍不清楚。将功能基因组学与家族性和散发性AD患者来源的iPSC分化为海马祖细胞、CA3神经元和脑类器官相结合，我们发现AP-1亚基c-Jun的上调触发了含有TE的基因组区域的解凝聚。这导致HERVK衍生的RNA-DNA杂合体的细胞质积累、cGAS-STING级联的激活和裂解的半胱天冬酶-3水平的增加，表明AD祖细胞和神经元中程序性细胞死亡的启动。值得注意的是，抑制c-Jun有效地阻断了所有这些下游分子过程，并挽救了AD祖细胞中的神经元死亡和受损的神经发生表型。我们的发现为确定治疗策略和生物标志物开辟了新的途径，以对抗疾病进展并在早期、症状前阶段诊断AD。最近有报道阿尔茨海默病和异染色质区转座因子（TE）的动员之间的联系。在这里，作者证明了先驱转录因子c-JUN（AP-1）的失调是阿尔茨海默病中异常转座因子动员、相关先天免疫2应答和神经发生受损的基础。
Adult neurogenic decline, inflammation, and neurodegeneration are phenotypic hallmarks of Alzheimer’s disease (AD). Mobilization of transposable elements (TEs) in heterochromatic regions was recently reported in AD, but the underlying mechanisms are still underappreciated. Combining functional genomics with the differentiation of familial and sporadic AD patient derived-iPSCs into hippocampal progenitors, CA3 neurons, and cerebral organoids, we found that the upregulation of the AP-1 subunit, c-Jun, triggers decondensation of genomic regions containing TEs. This leads to the cytoplasmic accumulation of HERVK-derived RNA-DNA hybrids, the activation of the cGAS-STING cascade, and increased levels of cleaved caspase-3, suggesting the initiation of programmed cell death in AD progenitors and neurons. Notably, inhibiting c-Jun effectively blocks all these downstream molecular processes and rescues neuronal death and the impaired neurogenesis phenotype in AD progenitors. Our findings open new avenues for identifying therapeutic strategies and biomarkers to counteract disease progression and diagnose AD in the early, pre-symptomatic stages. It has recently been reported a link between Alzheimer’s disease and mobilization of transposable elements (TEs) in heterochromatic regions. Here the authors demonstrate that dysregulation of the pioneer transcription factor c-JUN (AP-1) underlies aberrant transposable element mobilization, associated innate immune 2 response, and impaired neurogenesis in Alzheimer’s disease.
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影响因子：
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