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.

中文翻译：

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朊病毒的发病机制与 caspase-12 无关。

与蛋白质错误折叠相关的神经退行性疾病的致病机制尚不清楚。几项研究表明 ER 应激通路与神经退行性疾病有关，包括朊病毒病、肌萎缩侧索硬化、阿尔茨海默病和许多其他疾病。在克雅氏病患者的大脑和朊病毒病小鼠模型中观察到内质网应激反应和内质网应激反应分子伴侣的上调。特别是，caspase-12（一种定位于 ER 的半胱天冬酶）的加工与朊病毒疾病中的神经元细胞死亡相关。然而，caspase-12 对神经变性的贡献尚未在体内得到直接解决。我们确认 ER 应激被诱导并且 caspase-12 在传染性朊病毒病的小鼠模型中被蛋白水解处理。为了解决 caspase-12 在介导传染性朊病毒发病机制中的因果关系，我们给缺乏 caspase-12 的小鼠接种了朊病毒。蛋白酶 K 抗性 PrP 的存活、行为、病理学和积累在 caspase-12 敲除小鼠和对照小鼠之间没有区别，这表明 caspase-12 不是介导朊病毒蛋白错误折叠的神经毒性作用所必需的。