Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: Implications for prion replication and disease pathogenesis
Modulation of proteinase K-resistant prion protein in cells and infectious brain homogenate by redox iron: Implications for prion replication and disease pathogenesis
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DOI：
10.1091/mbc.e07-04-0317
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发表时间：
2007-09-01
影响因子：
3.3
通讯作者：
Singh, Neena
中科院分区：
文献类型：
--
作者：
Basu, Subhabrata;Mohan, Maradumane L.;Singh, Neena
所有朊病毒疾病中的主要传染性和病原体是细胞朊病毒蛋白（PrPC）的一种富含β折叠的亚型，称为PrP-瘙痒症（PrPSc）。一旦启动，PrPSc是自我复制的，对神经元细胞有毒，但潜在的机制仍不清楚。在这份报告中，我们表明，PrPC结合铁和转化为PrPSc样的形式（*PrPSc）时，人类神经母细胞瘤细胞暴露于无机源的氧化还原铁。由此产生的 *PrPSc本身具有氧化还原活性，并且它诱导额外的PrPc的转化，在没有脑源性PrPSc的情况下模拟 *PrPSc的传播。此外，从朊病毒病影响的人类和小鼠脑匀浆和羊瘙痒症感染的小鼠神经母细胞瘤细胞中铁的有限消耗导致蛋白酶K（PK）抗性PrPSc减少4至10倍，这意味着氧化还原铁在PK抗性PrPSc的产生、繁殖和稳定性中起作用。此外，我们证明增加的氧化还原活性亚铁在朊病毒病影响的大脑中的水平，这表明积累的PrPSc调制的脑铁稳态失衡和氧化还原活性性质的PrPSc的综合作用。这些数据提供了信息的复制和毒性的机制，由PrPSc，他们引起可预测的和治疗上可行的方式调节PrPSc负荷。
The principal infectious and pathogenic agent in all prion disorders is a beta-sheet-rich isoform of the cellular prion protein (PrPC) termed PrP-scrapie (PrPSc). Once initiated, PrPSc is self-replicating and toxic to neuronal cells, but the underlying mechanisms remain unclear. In this report, we demonstrate that PrPC binds iron and transforms to a PrPSc-like form (*PrPSc) when human neuroblastoma cells are exposed to an inorganic source of redox iron. The *PrPSc thus generated is itself redox active, and it induces the transformation of additional PrPc, simulating *PrPSc propagation in the absence of brain-derived PrPSc. Moreover, limited depletion of iron from prion disease-affected human and mouse brain homogenates and scrapie-infected mouse neuroblastoma cells results in 4- to 10-fold reduction in proteinase K (PK)-resistant PrPSc, implicating redox iron in the generation, propagation, and stability of PK-resistant PrPSc. Furthermore, we demonstrate increased redox-active ferrous iron levels in prion disease-affected brains, suggesting that accumulation of PrPSc is modulated by the combined effect of imbalance in brain iron homeostasis and the redox-active nature of PrPSc. These data provide information on the mechanism of replication and toxicity by PrPSc, and they evoke predictable and therapeutically amenable ways of modulating PrPSc load.