Caughey B, Raymond G J
Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
J Virol. 1993 Feb;67(2):643-50. doi: 10.1128/JVI.67.2.643-650.1993.
The accumulation of an abnormal, protease-resistant form of the protein PrP (PrP-res) in hosts with scrapie and related transmissible spongiform encephalopathies appears to be important in disease pathogenesis. To gain insight into the mechanism of PrP-res accumulation and the in vivo antiscrapie activity of certain polyanions, we have studied effects of sulfated glycans on PrP metabolism in scrapie-infected neuroblastoma cells. Pentosan polysulfate, like the amyloid-binding dye Congo red, potently inhibited the accumulation of PrP-res in these cells without apparent effects on the metabolism of the normal isoform. The inhibition was due primarily to prevention of new PrP-res accumulation rather than destabilization of preexisting PrP-res. PrP-res accumulation remained depressed in the cultures after removal of the inhibitors. The activities of other sulfated glycans, nonsulfated polyanions, dextran, and DEAE-dextran were compared with those of pentosan polysulfate and Congo red. This comparison provided evidence that the density of sulfation and molecular size are factors influencing anti-PrP-res activity of sulfated glycans. The relative potencies of these compounds corresponded well with their previously determined antiscrapie activities in vivo, suggesting that the prophylactic effects of sulfated polyanions may be due to inhibition of PrP-res accumulation. Since PrP-res amyloid is known to contain sulfated glycosaminoglycans, we reason that these inhibitors may competitively block an interaction between PrP and endogenous glycosaminoglycans that is essential for its accumulation in a protease-resistant, potentially amyloidogenic state.
在患有羊瘙痒症及相关传染性海绵状脑病的宿主体内，异常的、抗蛋白酶的蛋白质PrP（PrP-res）的积累似乎在疾病发病机制中起着重要作用。为了深入了解PrP-res积累的机制以及某些聚阴离子的体内抗羊瘙痒症活性，我们研究了硫酸化聚糖对羊瘙痒症感染的神经母细胞瘤细胞中PrP代谢的影响。戊聚糖多硫酸盐与淀粉样蛋白结合染料刚果红一样，能有效抑制这些细胞中PrP-res的积累，而对正常异构体的代谢没有明显影响。这种抑制主要是由于阻止了新的PrP-res积累，而不是使已存在的PrP-res不稳定。去除抑制剂后，培养物中PrP-res的积累仍处于较低水平。将其他硫酸化聚糖、非硫酸化聚阴离子、葡聚糖和DEAE-葡聚糖的活性与戊聚糖多硫酸盐和刚果红的活性进行了比较。这种比较提供了证据，表明硫酸化程度和分子大小是影响硫酸化聚糖抗PrP-res活性的因素。这些化合物的相对效力与其先前在体内确定的抗羊瘙痒症活性非常吻合，表明硫酸化聚阴离子的预防作用可能是由于抑制了PrP-res积累。由于已知PrP-res淀粉样蛋白含有硫酸化糖胺聚糖，我们推测这些抑制剂可能竞争性地阻断PrP与内源性糖胺聚糖之间的相互作用，而这种相互作用对于PrP在抗蛋白酶、潜在淀粉样生成状态下的积累至关重要。
