Research Center for Food Safety, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
Pharmaceuticals and Medical Devices Agency, Tokyo, Japan.
Curr Issues Mol Biol. 2020;36:67-88. doi: 10.21775/cimb.036.067. Epub 2019 Sep 27.
Lowering cellular prion protein (PrPC) levels in the brain is predicted to be a powerful therapeutic strategy for the prion disease. PrPC may act as an antiapoptotic agent by blocking some of the internal environmental factors that initiate apoptosis. Prion protein (PrP)-knockout methods provide powerful indications on the neuroprotective function of PrPC. Using PrPC-knockout cell lines, the inhibition of apoptosis through stress inducible protein1 (STI1) is mediated by PrPC-dependent superoxide dismutase (SOD) activation. Besides, PrP-knockout exhibited wide spread alterations of oscillatory activity in the olfactory bulb as well as altered paired-pulse plasticity at the dendrodendric synapse. Both the behavioural and electro-physiological phenotypes could be rescued by neuronal PrPC expression. Neuprotein Shadoo (Sho), similarly to PrPC, can prevent neuronal cell death induced by the expression of PrP△HD mutants, an artificial PrP mutant devoid of internal hydrophobic domain. Sho can efficiently protect cells against exito-toxin-induced cell death by glutamates. Sho and PrP seem to be dependent on similar domains, in particular N-terminal (N), and their internal hydrophobic domain. Sho△N and Sho△HD displayed a reduced stress-protective activity but are complex glycosylated and attached to the outer leaflet of the plasma membrane via glycosylphosphatidylinositol (GPI) anchor indicating that impaired activity is not due to incorrect cellular trafficking. In Sho, over-expressed mice showed large amyloid plaques not seen in wild-type mice. However, Shadoo is not a major modulator of abnormal prion protein (PrPSc) accumulation. Sho and PrP share a stress-protective activity. The ability to adopt a toxic conformation of PrPSc seems to be specific for PrP.
降低大脑中细胞朊蛋白 (PrPC) 的水平预计将成为朊病毒病的一种强大治疗策略。PrPC 可能通过阻断引发细胞凋亡的一些内部环境因素而发挥抗细胞凋亡作用。PrP 敲除方法为 PrPC 的神经保护功能提供了有力的证据。使用 PrPC 敲除细胞系，应激诱导蛋白 1 (STI1) 通过 PrPC 依赖性超氧化物歧化酶 (SOD) 激活抑制细胞凋亡。此外，PrP 敲除表现出嗅球中振荡活动的广泛改变以及树突树突突触中改变的成对脉冲可塑性。神经元 PrPC 表达可以挽救两者的行为和电生理表型。Neuprotein Shadoo（Sho）与 PrPC 类似，可以防止表达 PrP△HD 突变体（缺乏内部疏水区的人工 PrP 突变体）诱导的神经元细胞死亡。Sho 可以通过谷氨酸有效地保护细胞免受外毒素诱导的细胞死亡。Sho 和 PrP 似乎依赖于相似的结构域，特别是 N 端（N）及其内部疏水区。Sho△N 和 Sho△HD 显示出降低的应激保护活性，但它们是复杂糖基化的，并通过糖基磷脂酰肌醇 (GPI) 锚附着在质膜的外叶上，表明活性受损不是由于不正确的细胞转运。在 Sho 过表达的小鼠中，观察到大量淀粉样斑块，而在野生型小鼠中未见。然而，Shadoo 不是异常朊病毒蛋白 (PrPSc) 积累的主要调节剂。Sho 和 PrP 具有应激保护活性。采用 PrPSc 有毒构象的能力似乎是 PrP 特有的。
