Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation
Regulator of Calcineurin 1 (RCAN1) Facilitates Neuronal Apoptosis through Caspase-3 Activation
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DOI：
10.1074/jbc.m110.177519
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发表时间：
2011-03-18
影响因子：
4.8
通讯作者：
Song, Weihong
中科院分区：
文献类型：
--
作者：
Sun, Xiulian;Wu, Yili;Song, Weihong
唐氏综合征(DS)患者在中年后不可避免地会发展为阿尔茨海默病(AD)神经病理，这可能是由于DS患者的三重基因所致。阿尔茨海默病的神经病理特征包括神经炎性斑块、神经原纤维缠结和不同脑区的神经元丢失。AD和DS的神经退行性变的机制仍然不清楚。钙调神经磷酸酶1(RCAN1)参与了DS的发病机制。我们的数据显示RCAN1在DS和AD患者的皮质中表达升高。应激激素地塞米松可以激活RCAN1的表达。在RCAN1异构体1(RCAN1-1)启动子区域发现了一个功能性糖皮质激素反应元件，它能够介导RCAN1表达的上调。在这里，我们发现RCAN1-1在原代神经元中的过表达激活了caspase-9和caspase-3，并随后诱导了神经元的凋亡。此外，我们发现RCAN1-1的神经毒性可通过敲除caspase-3(-/-)神经元中的caspase-3而被抑制。我们的研究提供了一种新的机制，通过RCAN1作为应激和Aβ诱导的神经元死亡的中介，以及由于21号染色体上RCAN1基因的额外复制而导致的RCAN1的过度表达参与了DS的AD发病。
Individuals with Down syndrome (DS) will inevitably develop Alzheimer disease (AD) neuropathology sometime after middle age, which may be attributable to genes triplicated in individuals with DS. The characteristics of AD neuropathology include neuritic plaques, neurofibrillary tangles, and neuronal loss in various brain regions. The mechanism underlying neurodegeneration in AD and DS remains elusive. Regulator of calcineurin 1 (RCAN1) has been implicated in the pathogenesis of DS. Our data show that RCAN1 expression is elevated in the cortex of DS and AD patients. RCAN1 expression can be activated by the stress hormone dexamethasone. A functional glucocorticoid response element was identified in the RCAN1 isoform 1 (RCAN1-1) promoter region, which is able to mediate the up-regulation of RCAN1 expression. Here we show that overexpression of RCAN1-1 in primary neurons activates caspase-9 and caspase-3 and subsequently induces neuronal apoptosis. Furthermore, we found that the neurotoxicity of RCAN1-1 is inhibited by knock-out of caspase-3 in caspase-3(-/-) neurons. Our study provides a novel mechanism by which RCAN1 functions as a mediator of stress- and A beta-induced neuronal death, and overexpression of RCAN1 due to an extra copy of the RCAN1 gene on chromosome 21 contributes to AD pathogenesis in DS.