Department of Neuropathology, Heinrich Heine University Düsseldorf, Moorenstrasse 5, 40225 Düsseldorf, Germany.
Neurosci Lett. 2010 Jan 18;469(1):122-6. doi: 10.1016/j.neulet.2009.11.057. Epub 2009 Nov 27.
Beneficial effects of tocopherols, or vitamin E, on degenerative brain conditions have been attributed mainly to their antioxidant effects. Non-antioxidant effects of the tocopherols have been shown to be mediated by inhibition of protein kinase C (PKC) signaling. Prion disease is a paradigmatic protein conformational disease characterized by the induced conversion of a normal host protein PrP(C) to adopt a pathogenic conformation PrP(Sc). The molecular regulation of prion replication is poorly understood. Here, we show that tocopherols inhibit prion replication by a structure-activity relationship for antiprion activity independent of antioxidant activity with tocopherol succinate (TS) posessing highest EC(50) at 7 microM. Only TS but not an equally antiprion active PKC inhibitor could be partially antagonized by substochiometric 1 nM rapamycin suggesting that there are pathways via mammalian target of rapamycin (mTOR) that interfere with tocopherol's biological effects. Interaction with the mTOR pathway is a yet undescribed characteristic of tocopherol derivatives, potentially significant for pathophysiological processes other than prion propagation.
生育酚（即维生素 E）对退行性脑疾病的有益作用主要归因于其抗氧化作用。生育酚的非抗氧化作用已被证明是通过抑制蛋白激酶 C（PKC）信号转导来介导的。朊病毒病是一种典型的蛋白质构象疾病，其特征是正常宿主蛋白 PrP(C)被诱导转化为致病性构象 PrP(Sc)。朊病毒复制的分子调控机制尚不清楚。在这里，我们表明生育酚通过与抗氧化活性无关的抗朊病毒活性的构效关系抑制朊病毒复制，生育酚琥珀酸（TS）具有最高的 EC(50)，为 7 微摩尔。只有 TS，而不是同样具有抗朊病毒活性的 PKC 抑制剂，可以被亚化学计量的 1 纳米雷帕霉素部分拮抗，这表明存在通过哺乳动物雷帕霉素靶蛋白（mTOR）的途径干扰生育酚的生物学效应。与 mTOR 途径的相互作用是生育酚衍生物的一个尚未描述的特征，对于朊病毒传播以外的病理生理过程可能具有重要意义。
