Strain-Dependent Effect of Macroautophagy on Abnormally Folded Prion Protein Degradation in Infected Neuronal Cells.

Prion diseases are neurodegenerative disorders caused by the accumulation of abnormal prion protein (PrPSc) in the central nervous system. With the aim of elucidating the mechanism underlying the accumulation and degradation of PrPSc, we investigated the role of autophagy in its degradation, using cultured cells stably infected with distinct prion strains. The effects of pharmacological compounds that inhibit or stimulate the cellular signal transduction pathways that mediate autophagy during PrPSc degradation were evaluated. The accumulation of PrPSc in cells persistently infected with the prion strain Fukuoka-1 (FK), derived from a patient with Gerstmann–Sträussler–Scheinker syndrome, was significantly increased in cultures treated with the macroautophagy inhibitor 3-methyladenine (3MA) but substantially reduced in those treated with the macroautophagy inducer rapamycin. The decrease in FK-derived PrPSc levels was mediated, at least in part, by the phosphatidylinositol 3-kinase/MEK signalling pathway. By contrast, neither rapamycin nor 3MA had any apparently effect on PrPSc from either the 22L or the Chandler strain, indicating that the degradation of PrPSc in host cells might be strain-dependent.

朊病毒病是由异常朊病毒蛋白（PrPSc）在中枢神经系统中积聚所引起的神经退行性疾病。为了阐明PrPSc积聚和降解的潜在机制，我们利用稳定感染不同朊病毒株的培养细胞，研究了自噬在其降解中的作用。评估了在PrPSc降解过程中抑制或刺激介导自噬的细胞信号转导通路的药物化合物的效果。在持续感染源自格斯特曼 - 施特劳斯勒 - 辛克综合征患者的福冈 - 1（FK）朊病毒株的细胞中，PrPSc的积聚在经巨自噬抑制剂3 - 甲基腺嘌呤（3MA）处理的培养物中显著增加，而在经巨自噬诱导剂雷帕霉素处理的培养物中则大幅减少。FK来源的PrPSc水平的降低至少部分是由磷脂酰肌醇3 - 激酶/MEK信号通路介导的。相比之下，雷帕霉素和3MA对22L或钱德勒株的PrPSc均无明显影响，这表明宿主细胞中PrPSc的降解可能具有株依赖性。