The amyloid precursor protein (APP)-cytoplasmic fragment generated by γ-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture
The amyloid precursor protein (APP)-cytoplasmic fragment generated by γ-secretase is rapidly degraded but distributes partially in a nuclear fraction of neurones in culture
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DOI：
10.1046/j.1471-4159.2001.00516.x
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发表时间：
2001-09-01
影响因子：
4.7
通讯作者：
De Strooper, B
中科院分区：
文献类型：
--
作者：
Cupers, P;Orlans, I;De Strooper, B
γ-分泌酶裂解是从淀粉样前体蛋白（APP）产生β-淀粉样肽（A β）的最后一步。阿尔茨海默病患者大脑中的淀粉样斑块中A β沉淀。相反，与A β一起产生的细胞内APP羧基末端残端的命运只有很少的记录。APP和其他跨膜蛋白（如SREBP和Notch）的加工之间的相似性表明，这种细胞内片段可能具有重要的信号功能。我们在这里证明，APP-C59在幼仓鼠肾细胞或神经元原代培养物中过表达时，通过一种不受内体/溶酶体或蛋白酶体抑制剂抑制的机制迅速降解（半衰期类似于5分钟）。此外，APP-C59与DNA结合蛋白Fe 65结合，尽管这不会增加APP-C59的半衰期。最后，我们证明了APP-C59的一部分被重新分配到核洗涤剂不溶性颗粒中，其中也存在转录因子SP1。总的来说，我们的研究结果加强了Notch和APP加工之间的相似性，并表明APP胞内结构域，如Notch胞内结构域，可能在从质膜到细胞核的信号事件中发挥作用。
The gamma -secretase cleavage is the last step in the generation of the beta -amyloid peptide (A beta) from the amyloid precursor protein (APP). The A beta precipitates in the amyloid plaques in the brain of Alzheimer's disease patients. The fate of the intracellular APP carboxy-terminal stub generated together with A beta has been, in contrast, only poorly documented. The analogies between the processing of APP and other transmembrane proteins like SREBP and Notch suggests that this intracellular fragment could have important signalling functions. We demonstrate here that APP-C59 is rapidly degraded (half-life similar to5 min) when overexpressed in baby hamster kidney cells or primary cultures of neurones by a mechanism that is not inhibited by endosomal/lysosomal or proteasome inhibitors. Furthermore, APP-C59 binds to the DNA binding protein Fe65, although this does not increase the half-life of APP-C59. Finally, we demonstrate that a fraction of APP-C59 becomes redistributed to the nuclear detergent-insoluble pellet, in which the transcription factor SP1 is also present. Overall our results reinforce the analogy between Notch and APP processing, and suggest that the APP intracellular domain, like the Notch intracellular domain, could have a role in signalling events from the plasma membrane to the nucleus.