Sandberg Malin K, Al-Doujaily Huda, Sharps Bernadette, De Oliveira Michael Wiggins, Schmidt Christian, Richard-Londt Angela, Lyall Sarah, Linehan Jacqueline M, Brandner Sebastian, Wadsworth Jonathan D F, Clarke Anthony R, Collinge John
MRC Prion Unit and Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK.
Nat Commun. 2014 Jul 9;5:4347. doi: 10.1038/ncomms5347.
Prions are lethal infectious agents thought to consist of multi-chain forms (PrP(Sc)) of misfolded cellular prion protein (PrP(C)). Prion propagation proceeds in two distinct mechanistic phases: an exponential phase 1, which rapidly reaches a fixed level of infectivity irrespective of PrP(C) expression level, and a plateau (phase 2), which continues until clinical onset with duration inversely proportional to PrP(C) expression level. We hypothesized that neurotoxicity relates to distinct neurotoxic species produced following a pathway switch when prion levels saturate. Here we show a linear increase of proteinase K-sensitive PrP isoforms distinct from classical PrP(Sc) at a rate proportional to PrP(C) concentration, commencing at the phase transition and rising until clinical onset. The unaltered level of total PrP during phase 1, when prion infectivity increases a million-fold, indicates that prions comprise a small minority of total PrP. This is consistent with PrP(C) concentration not being rate limiting to exponential prion propagation and neurotoxicity relating to critical concentrations of alternate PrP isoforms whose production is PrP(C) concentration dependent.
朊病毒是致死性感染因子，被认为由错误折叠的细胞朊蛋白（PrP(C)）的多链形式（PrP(Sc)）组成。朊病毒的传播过程分为两个不同的机制阶段：指数期1，无论PrP(C)表达水平如何，感染性都会迅速达到固定水平；平台期（阶段2），持续到临床发病，持续时间与PrP(C)表达水平成反比。我们假设，当朊病毒水平饱和时，神经毒性与途径转换后产生的不同神经毒性物种有关。在此，我们展示了蛋白酶K敏感的PrP异构体的线性增加，这些异构体不同于经典的PrP(Sc)，其增加速率与PrP(C)浓度成正比，从相变开始，一直上升到临床发病。在阶段1，当朊病毒感染性增加一百万倍时，总PrP水平未改变，这表明朊病毒在总PrP中只占一小部分。这与PrP(C)浓度不是指数期朊病毒传播的速率限制因素以及神经毒性与替代PrP异构体的临界浓度有关一致，这些异构体的产生依赖于PrP(C)浓度。
