State Key Laboratories for Agrobiotechnology, National Animal Transmissible Spongiform Encephalopathy Laboratory, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China.
Acta Biochim Biophys Sin (Shanghai). 2013 Jun;45(6):477-84. doi: 10.1093/abbs/gmt020. Epub 2013 Feb 28.
Prion diseases are associated with the conformational conversion of cellular prion protein (PrP(C)) to pathological β-sheet isoforms (PrP(Sc)), which is the infectious agent beyond comprehension. Increasing evidence indicated that an unknown toxic gain of function of PrP(sc) underlies neuronal death. Conversely, strong evidence indicated that cellular prion protein might be directly cytotoxic by mediating neurotoxic signaling of β-sheet-rich conformers independent of prion replication. Furthermore, the common properties of β-sheet-rich isoform such as PrP(Sc) and β amyloid protein become the lynchpin that interprets the general pathological mechanism of protein misfolding diseases. Dysfunction of the ubiquitin-proteasome system (UPS) has been implicated in various protein misfolding diseases. However, the mechanisms of this impairment remain unknown in many cases. In prion disease, prion-infected mouse brains have increased levels of ubiquitin conjugates, which correlate with decreased proteasome function. Both PrP(C) and PrP(Sc) accumulate in cells after proteasome inhibition, which leads to increased cell death. A direct interaction between 20S core particle and PrP isoforms was demonstrated. Here we review the ability of misfolded PrP and UPS to affect each other, which might contribute to the pathological features of prion-mediated neurodegeneration.
朊病毒病与细胞朊蛋白（PrP(C)）的构象转换有关，其转换为病理性β-折叠异构体（PrP(Sc)），而这种构象转换是无法理解的感染因子。越来越多的证据表明，PrP(sc)未知的毒性功能获得是神经元死亡的基础。相反，强有力的证据表明，细胞朊蛋白可能通过介导富含β-折叠的构象的神经毒性信号直接具有细胞毒性，而与朊病毒复制无关。此外，富含β-折叠的异构体（如 PrP(Sc)和β淀粉样蛋白）的共同特性成为解释蛋白质错误折叠疾病一般病理机制的关键。泛素-蛋白酶体系统（UPS）的功能障碍与各种蛋白质错误折叠疾病有关。然而，在许多情况下，这种损伤的机制仍然未知。在朊病毒病中，感染朊病毒的小鼠大脑中泛素缀合物的水平增加，这与蛋白酶体功能降低有关。蛋白酶体抑制后，PrP(C)和 PrP(Sc)都在细胞中积累，导致细胞死亡增加。已经证明 20S 核心颗粒与 PrP 异构体之间存在直接相互作用。在这里，我们回顾了错误折叠的 PrP 和 UPS 相互影响的能力，这可能有助于朊病毒介导的神经退行性变的病理特征。
