Prion Pathogenesis is Independent of Caspase-12
Prion Pathogenesis is Independent of Caspase-12
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DOI：
10.4161/pri.1.4.5551
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发表时间：
2007-10-01
期刊：
影响因子：
2.3
通讯作者：
Lindquist, Susan
中科院分区：
文献类型：
--
作者：
Steele, Andrew D.;Hetz, Claudio;Lindquist, Susan
与蛋白质错误折叠相关的神经退行性疾病的致病机制(S)尚不清楚。几项研究表明，内质网应激通路与神经退行性疾病有关，包括Pron病、肌萎缩侧索硬化症、阿尔茨海默病和许多其他疾病。内质网应激反应和内质网应激反应伴侣蛋白的上调是在克雅氏病患者的大脑中观察到的，在普恩病鼠模型中也观察到了。特别是，caspase-12是一种ER定位的caspase，它的处理与Pron病中神经细胞的死亡有关。然而，caspase-12在神经退行性变中的作用还没有直接在体内得到解决。我们证实，在传染性Pron病的小鼠模型中，内质网应激被诱导，caspase-12被蛋白水解性处理。为了阐明caspase-12在介导传染性普恩病毒发病机制中的因果关系，我们将caspase-12基因缺陷的小鼠接种到普恩病毒中。在caspase-12基因敲除小鼠和对照小鼠之间，caspase-12基因敲除小鼠的存活、行为、病理和对蛋白酶K耐药的PrP的积聚没有区别，这表明caspase-12不是介导PrP蛋白错误折叠的神经毒性效应所必需的。
The pathogenic mechanism(s) underlying neurodegenerative diseases associated with protein misfolding is unclear. Several studies have implicated ER stress pathways in neurodegenerative conditions, including prion disease, amyotrophic lateral sclerosis, Alzheimer's disease and many others. The ER stress response and upregulation of ER stress-responsive chaperones is observed in the brains of patients affected with Creutzfeldt-Jacob disease and in mouse models of prion diseases. In particular, the processing of caspase-12, an ER-localized caspase, correlates with neuronal cell death in prion disease. However, the contribution of caspase-12 to neurodegeneration has not been directly addressed in vivo. We confirm that ER stress is induced and that caspase-12 is proteolytically processed in a murine model of infectious prion disease. To address the causality of caspase-12 in mediating infectious prion pathogenesis, we inoculated mice deficient in caspase-12 with prions. The survival, behavior, pathology and accumulation of proteinase K-resistant PrP are indistinguishable between caspase-12 knockout and control mice, suggesting that caspase-12 is not necessary for mediating the neurotoxic effects of prion protein misfolding.