Löfgren Kajsa, Wahlström Anna, Lundberg Pontus, Langel Ulo, Gräslund Astrid, Bedecs Katarina
Department of Biochemistry and Biophysics, The Arrhenius Laboratories, Stockholm University, SE-106 91 Stockholm, Sweden.
FASEB J. 2008 Jul;22(7):2177-84. doi: 10.1096/fj.07-099549. Epub 2008 Feb 22.
In prion diseases, the cellular prion protein (PrP(C)) becomes misfolded into the pathogenic scrapie isoform (PrP(Sc)) responsible for prion infectivity. We show here that peptides derived from the prion protein N terminus have potent antiprion effects. These peptides are composed of a hydrophobic sequence followed by a basic segment. They are known to have cell-penetrating ability like regular cell-penetrating peptides (CPPs), short peptides that can penetrate cellular membranes. Healthy (GT1-1) and scrapie-infected (ScGT1-1) mouse neuronal hypothalamic cells were treated with various CPPs, including the prion protein-derived CPPs. Lysates were analyzed for altered protein levels of PrP(C) or PrP(Sc). Treatment with the prion protein-derived CPPs mouse mPrP(1-28) or bovine bPrP(1-30) significantly reduced PrP(Sc) levels in prion-infected cells but had no effect on PrP(C) levels in noninfected cells. Further, presence of prion protein-derived CPPs significantly prolonged the time before infection was manifested when infecting GT1-1 cells with scrapie. Treatment with other CPPs (penetratin, transportan-10, or poly-L-arginine) or prion protein-derived peptides lacking CPP function (mPrP(23-28,) mPrP(19-30,) or mPrP(23-50)) had no effect on PrP(Sc) levels. The results suggest a mechanism by which the signal sequence guides the prion protein-derived CPP into a cellular compartment, where the basic segment binds specifically to PrP(Sc) and disables formation of prions.
在朊病毒疾病中，细胞朊蛋白（PrP(C)）会错误折叠成具有朊病毒感染性的致病性瘙痒病异构体（PrP(Sc)）。我们在此表明，源自朊蛋白N端的肽具有强大的抗朊病毒作用。这些肽由一个疏水序列和一个碱性片段组成。已知它们具有像常规细胞穿透肽（CPPs）一样的细胞穿透能力，常规细胞穿透肽是能穿透细胞膜的短肽。用包括源自朊蛋白的CPPs在内的各种CPPs处理健康的（GT1-1）和感染瘙痒病的（ScGT1-1）小鼠下丘脑神经细胞。分析裂解物中PrP(C)或PrP(Sc)的蛋白水平变化。用源自朊蛋白的CPPs小鼠mPrP(1-28)或牛bPrP(1-30)处理可显著降低朊病毒感染细胞中的PrP(Sc)水平，但对未感染细胞中的PrP(C)水平没有影响。此外，当用瘙痒病感染GT1-1细胞时，源自朊蛋白的CPPs的存在显著延长了感染显现前的时间。用其他CPPs（穿膜肽、转运蛋白-10或聚-L-精氨酸）或缺乏CPP功能的源自朊蛋白的肽（mPrP(23-28)、mPrP(19-30)或mPrP(23-50)）处理对PrP(Sc)水平没有影响。结果提示了一种机制，即信号序列将源自朊蛋白的CPP引导至细胞区室，在该区室中碱性片段与PrP(Sc)特异性结合并阻止朊病毒的形成。
