Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.
Association of AICD and Fe65 with Hirano bodies reduces transcriptional activation and initiation of apoptosis.
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DOI：
10.1016/j.neurobiolaging.2010.01.003
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发表时间：
2011-12
影响因子：
4.2
通讯作者：
Fechheimer, Marcus
中科院分区：
文献类型：
--
作者：
Ha, Sangdeuk;Furukawa, Ruth;Fechheimer, Marcus
关键词：
平野小体是一种胞质包涵体，主要存在于中枢神经系统，与包括衰老和阿尔茨海默病(AD)在内的各种疾病有关。由于大多数对平野小体的研究都是在死后标本中进行的，因此还没有对平野小体的生理作用进行研究。星形细胞瘤H4细胞被用来检验平野小体与淀粉样蛋白β前体蛋白的C末端片段相互作用并调节信号的假说。我们通过免疫荧光和免疫沉淀证明了模型平野小体积聚了AICD。由于AICD对转录的刺激依赖于其与核适配蛋白Fe65的相互作用，因此我们研究了Fe65的定位，并采用双荧光素酶报告基因分析方法来检测平野小体对AICD和Fe65依赖的基因表达调控的影响。我们发现AICD和Fe65在模型平野体中是共定位的。模型平野小体还下调AICD依赖的细胞凋亡以及AICD和Fe65依赖的转录活性。因此，AICD和Fe65与平野小体的结合阻碍了它们促进细胞凋亡和调节转录的功能。
Hirano bodies are cytoplasmic inclusions predominantly found in the central nervous system associated with various conditions including aging and Alzheimer's disease (AD). Since most studies of Hirano bodies have been performed in post-mortem samples, the physiological roles of Hirano bodies have not been investigated. Astrocytoma H4 cells were employed to test the hypothesis that Hirano bodies interact with and modulate signaling by the C-terminal fragment of amyloid-β precursor protein (AICD). We demonstrated by immunofluorescence and immunoprecipitation that model Hirano bodies accumulate AICD. Since stimulation of transcription by AICD is dependent on its interaction with the nuclear adaptor protein Fe65, we examined localization of Fe65, and employed a dual luciferase reporter assay to test the effects of Hirano bodies on AICD- and Fe65-dependent modulation of gene expression. We find that both AICD and Fe65 are co-localized in model Hirano bodies. Model Hirano bodies also down-regulate both AICD-dependent apoptosis and AICD- and Fe65-dependent transcriptional activity. Thus, association of AICD and Fe65 with Hirano bodies impedes their function in promoting apoptosis and modulating transcription.
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