The ER stress factor XBP1s prevents amyloid-β neurotoxicity
The ER stress factor XBP1s prevents amyloid-β neurotoxicity
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DOI：
10.1093/hmg/ddr100
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发表时间：
2011-06-01
影响因子：
3.5
通讯作者：
Fernandez-Funez, Pedro
中科院分区：
文献类型：
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作者：
Casas-Tinto, Sergio;Zhang, Yan;Fernandez-Funez, Pedro
阿尔茨海默病(AD)是一种无法治愈的神经退行性疾病，临床特征为进行性认知功能障碍。AD脑中一个显著的病理特征是淀粉样β1-42肽(Aβ)的异常积聚，但介导Aβ神经毒性的确切途径仍然是个谜。内质网(ER)应激在AD过程中被诱导，并间接地被认为是Aβ神经毒性的中介。我们在这里报道，Aβ在转基因果蝇和哺乳动物培养的神经元中激活内质网应激反应因子X盒结合蛋白1(XBP1)，产生其活性形式XBP1s。XBP1在两种不同的AD模型中显示出神经保护活性，表达Aβ的苍蝇和用Aβ寡聚体处理的哺乳动物培养神经元。为了确定XBP1s介导神经保护的机制，我们发现，在用Aβ寡聚体处理的PC12细胞中，XBP1s阻止了胞浆中游离钙的积累。这种保护作用可以通过下调Ryanodine钙通道的一个特定亚型RyR3来实现。为了支持这一观察结果，果蝇中唯一的Ryanodine受体(RyR)突变也抑制了Aβ神经毒性，表明两种AD模型之间的保守机制。这些结果强调了XBP1在Aβ毒性中的功能相关性，并揭示了XBP1和RyR作为AD治疗靶点的潜力。
Alzheimer's disease (AD) is an incurable neurodegenerative disorder clinically characterized by progressive cognitive impairment. A prominent pathologic hallmark in the AD brain is the abnormal accumulation of the amyloid-beta 1-42 peptide (A beta), but the exact pathways mediating A beta neurotoxicity remain enigmatic. Endoplasmic reticulum (ER) stress is induced during AD, and has been indirectly implicated as a mediator of A beta neurotoxicity. We report here that A beta activates the ER stress response factor X-box binding protein 1 (XBP1) in transgenic flies and in mammalian cultured neurons, yielding its active form, the transcription factor XBP1s. XBP1s shows neuroprotective activity in two different AD models, flies expressing A beta and mammalian cultured neurons treated with A beta oligomers. Trying to identify the mechanisms mediating XBP1s neuroprotection, we found that in PC12 cells treated with A beta oligomers, XBP1s prevents the accumulation of free calcium (Ca2+) in the cytosol. This protective activity can be mediated by the downregulation of a specific isoform of the ryanodine Ca2+ channel, RyR3. In support of this observation, a mutation in the only ryanodine receptor (RyR) in flies also suppresses A beta neurotoxicity, indicating the conserved mechanisms between the two AD models. These results underscore the functional relevance of XBP1s in A beta toxicity, and uncover the potential of XBP1 and RyR as targets for AD therapeutics.