Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function.
Characterization of a series of 4-aminoquinolines that stimulate caspase-7 mediated cleavage of TDP-43 and inhibit its function.
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DOI：
10.1016/j.biochi.2012.05.020
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发表时间：
2012-09
期刊：
影响因子：
3.9
通讯作者：
Reitz, Allen B.
中科院分区：
文献类型：
--
作者：
Cassel, Joel A.;McDonnell, Mark E.;Velvadapu, Venkata;Andrianov, Vyacheslav;Reitz, Allen B.
异源核糖核蛋白 TAR DNA 结合蛋白 43 (TDP-43) 的功能障碍与肌萎缩侧索硬化症 (ALS) 和额颞叶变性 (FTLD) 等疾病中的神经退行性疾病相关。在这里，我们研究了一系列对 TDP-43 具有亲和力的 4-氨基喹啉对 caspase-7 诱导的 TDP-43 裂解和 TDP-43 细胞功能的影响。这些化合物是生物素化 TG6 与 TDP-43 结合的混合抑制剂，可与游离和占据的 TDP-43 结合。在这些化合物存在的情况下孵育 TDP-43 和 caspase-7 会刺激 caspase-7 介导的 TDP-43 裂解。这种效应被寡核苷酸 TG12 拮抗，通过 TDP-43 变性来阻止，并且表现出与与 TDP-43 结合的 bt-TG6 置换相似的结构与功能关系。此外，这些化合物不影响 caspase-7 酶活性。在人神经胶质瘤 H4 细胞中，这些化合物通过 caspase 依赖性机制降低了 TDP-43 的水平并增加了 TDP-43 C 末端片段。随后的实验证明，这是由于半胱天冬酶 3 和 7 的诱导导致 H4 细胞中 PARP 裂解增加，并且在测试 bt-TG6 结合置换的化合物中效力的顺序相似。暴露于这些化合物还减少了 HDAC6、ATG7 并增加了 LC3B，这与其他研究人员描述的 TDP-43 siRNA 的作用一致。这些数据表明，此类化合物可能是有用的生化探针，可进一步了解 TDP-43 的正常和病理功能，以及半胱天冬酶促进的其裂解和代谢。
Dysfunction of the heterogeneous ribonucleoprotein TAR DNA binding protein 43 (TDP-43) is associated with neurodegeneration in diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). Here we examine the effects of a series of 4-aminoquinolines with affinity for TDP-43 upon caspase-7-induced cleavage of TDP-43 and TDP-43 cellular function. These compounds were mixed inhibitors of biotinylated TG6 binding to TDP-43, binding to both free and occupied TDP-43. Incubation of TDP-43 and caspase-7 in the presence of these compounds stimulated caspase-7 mediated cleavage of TDP-43. This effect was antagonized by the oligonucleotide TG12, prevented by denaturing TDP-43, and exhibited a similar relation of structure to function as for the displacement of bt-TG6 binding to TDP-43. In addition, the compounds did not affect caspase-7 enzyme activity. In human neuroglioma H4 cells, these compounds lowered levels of TDP-43 and increased TDP-43 C-terminal fragments via a caspase-dependent mechanism. Subsequent experiments demonstrated that this was due to induction of caspases 3 and 7 leading to increased PARP cleavage in H4 cells with similar rank order of the potency among the compounds tests for displacement of bt-TG6 binding. Exposure to these compounds also reduced HDAC6, ATG7, and increased LC3B, consistent with the effects of TDP-43 siRNA described by other investigators. These data suggest that such compounds may be useful biochemical probes to further understand both the normal and pathological functions of TDP-43, and its cleavage and metabolism promoted by caspases.
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影响因子：
38.1
作者：
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通讯作者：
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影响因子：
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