Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein
Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein
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DOI：
10.1093/emboj/cdg537
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发表时间：
2003-10-15
期刊：
影响因子：
11.4
通讯作者：
Soto, C
中科院分区：
文献类型：
--
作者：
Hetz, C;Russelakis-Carneiro, M;Soto, C
朊病毒疾病的特征在于错误折叠的朊病毒蛋白（PrPSc）的积累和通过细胞凋亡引起的神经元死亡。在这里，我们表明，纳摩尔浓度的纯化PrPSc从小鼠瘙痒症脑诱导N2 A神经母细胞瘤细胞凋亡。PrPSc毒性与内质网（ER）释放的细胞内钙增加和几种ER伴侣的上调有关。在用PrPSc处理的细胞中检测到胱天蛋白酶-12活化，并且通过过表达胱天蛋白酶-12的催化突变体或ER靶向Bcl-2嵌合蛋白来抑制细胞死亡。羊瘙痒病感染的N2 A细胞比未感染的细胞更容易受到ER应激和PrPSc毒性的影响。在羊瘙痒病感染的小鼠中，在不同脑区的组织学和生物化学分析中观察到半胱天冬酶-12活化和神经元损失之间的相关性。朊病毒复制的程度与ER应激伴侣蛋白的上调密切相关。在患有散发性和变异型克雅氏病的人中观察到类似的结果，首次暗示了体内神经退行性疾病中的半胱天冬酶-12依赖性途径，从而为治疗朊病毒疾病提供了新的潜在靶点。
Prion diseases are characterized by accumulation of misfolded prion protein (PrPSc), and neuronal death by apoptosis. Here we show that nanomolar concentrations of purified PrPSc from mouse scrapie brain induce apoptosis of N2A neuroblastoma cells. PrPSc toxicity was associated with an increase of intracellular calcium released from endoplasmic reticulum (ER) and up-regulation of several ER chaperones. Caspase-12 activation was detected in cells treated with PrPSc, and cellular death was inhibited by overexpression of a catalytic mutant of caspase-12 or an ER-targeted Bcl-2 chimeric protein. Scrapie-infected N2A cells were more susceptible to ER-stress and to PrPSc toxicity than non-infected cells. In scrapie-infected mice a correlation between caspase-12 activation and neuronal loss was observed in histological and biochemical analyses of different brain areas. The extent of prion replication was closely correlated with the up-regulation of ER-stress chaperone proteins. Similar results were observed in humans affected with sporadic and variant Creutzfeldt-Jakob disease, implicating for the first time the caspase-12 dependent pathway in a neurodegenerative disease in vivo, and thus offering novel potential targets for the treatment of prion disorders.