Prion peptide 106-126 modulates the aggregation of cellular prion protein and induces the synthesis of potentially neurotoxic transmembrane PrP
Prion peptide 106-126 modulates the aggregation of cellular prion protein and induces the synthesis of potentially neurotoxic transmembrane PrP
复制标题
DOI：
10.1074/jbc.m104345200
复制
发表时间：
2002-01-18
影响因子：
4.8
通讯作者：
Singh, N
中科院分区：
文献类型：
--
作者：
Gu, YP;Fujioka, H;Singh, N
在感染性和家族性朊病毒疾病中，神经变性通常没有明显的瘙痒症朊病毒蛋白（PrPSc）沉积，而瘙痒症朊病毒蛋白是朊病毒疾病中神经元死亡的主要原因。在这种情况下，神经毒性必须由细胞死亡的替代途径介导。一种这样的途径是通过PrP的跨膜形式。我们已经研究了朊病毒蛋白聚集体的细胞内积累和随后的跨膜朊病毒蛋白在细胞模型中的上调之间的关系。在这里，我们报告说，暴露的神经母细胞瘤细胞的朊病毒肽106-126催化细胞朊病毒蛋白的聚集到一个弱的蛋白酶K-抗性形式，并诱导跨膜朊病毒蛋白的合成，在某些朊病毒疾病的神经毒性的介质。新合成的跨膜朊病毒蛋白的N末端在内质网的胞质表面上自发地裂解，并且截短的C末端片段在细胞表面上积累。我们的研究结果表明，朊病毒疾病的神经毒性是介导的一个复杂的途径，涉及跨膜朊病毒蛋白，而不是由沉积物的聚集和蛋白酶K-抗朊蛋白。
In infectious and familial prion disorders, neurodegeneration is often seen without obvious deposits of the scrapie prion protein (PrPSc), the principal cause of neuronal death in prion disorders. In such cases, neurotoxicity must be mediated by alternative pathways of cell death. One such pathway is through a transmembrane form of PrP. We have investigated the relationship between intracellular accumulation of prion protein aggregates and the consequent up-regulation of transmembrane prion protein in a cell model. Here, we report that exposure of neuroblastoma cells to the prion peptide 106-126 catalyzes the aggregation of cellular prion protein to a weakly proteinase K-resistant form and induces the synthesis of transmembrane prion protein, the proposed mediator of neurotoxicity in certain prion disorders. The N terminus of newly synthesized transmembrane prion protein is cleaved spontaneously on the cytosolic face of the endoplasmic reticulum, and the truncated C-terminal fragment accumulates on the cell surface. Our results suggest that neurotoxicity in prion disorders is mediated by a complex pathway involving transmembrane prion protein and not by deposits of aggregated and proteinase K-resistant PrP alone.