Prion diseases are fatal infectious neurodegenerative disorders in human and animals caused by misfolding of the cellular prion protein (PrPC) into the infectious isoform PrPSc. These diseases have the potential to transmit within or between species, and no cure is available to date. Targeting the unfolded protein response (UPR) as an anti-prion therapeutic approach has been widely reported for prion diseases. Here, we describe the anti-prion effect of the chemical compound Sephin1 which has been shown to protect in mouse models of protein misfolding diseases including amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) by selectively inhibiting the stress-induced regulatory subunit of protein phosphatase 1, thus prolonging eIF2α phosphorylation. We show here that Sephin1 dose and time dependently reduced PrPSc in different neuronal cell lines which were persistently infected with various prion strains. In addition, prion seeding activity was reduced in Sephin1-treated cells. Importantly, we found that Sephin1 significantly overcame the endoplasmic reticulum (ER) stress induced in treated cells, as measured by lower expression of stress-induced aberrant prion protein. In a mouse model of prion infection, intraperitoneal treatment with Sephin1 significantly prolonged survival of prion-infected mice. When combining Sephin1 with the neuroprotective drug metformin, the survival of prion-infected mice was also prolonged. These results suggest that Sephin1 could be a potential anti-prion drug selectively targeting one component of the UPR pathway.

中文翻译：

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Sephin1 减少朊病毒感染细胞和动物模型中的朊病毒感染。

朊病毒疾病是人类和动物的致命传染性神经退行性疾病，由细胞朊病毒蛋白 (PrPC) 错误折叠成传染性同种型 PrPSc 引起。这些疾病有可能在物种内部或物种之间传播，迄今为止还没有治愈方法。靶向未折叠蛋白反应 (UPR) 作为一种抗朊病毒治疗方法已被广泛报道用于朊病毒疾病。在这里，我们描述了化合物 Sephin1 的抗朊病毒作用，该化合物已被证明可以通过选择性抑制应激诱导的调节亚基来保护包括肌萎缩侧索硬化症 (ALS) 和多发性硬化症 (MS) 在内的蛋白质错误折叠疾病的小鼠模型。蛋白磷酸酶 1，从而延长 eIF2α 磷酸化。我们在此表明​​，在持续感染各种朊病毒株的不同神经元细胞系中，Sephin1 剂量和时间依赖性地减少 PrPSc。此外，在 Sephin1 处理的细胞中，朊病毒播种活性降低。重要的是，我们发现 Sephin1 显着克服了在处理细胞中诱导的内质网 (ER) 应激，这是通过应激诱导的异常朊病毒蛋白的较低表达来衡量的。在朊病毒感染的小鼠模型中，用 Sephin1 进行腹腔内治疗可显着延长感染朊病毒的小鼠的存活时间。当将 Sephin1 与神经保护药物二甲双胍结合使用时，感染朊病毒的小鼠的存活期也得到了延长。这些结果表明，Sephin1 可能是一种潜在的抗朊病毒药物，选择性地靶向 UPR 通路的一个成分。