Caughey B, Race R E
Laboratory of Persistent Viral Diseases, NIH Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
Ann N Y Acad Sci. 1994 Jun 6;724:290-5. doi: 10.1111/j.1749-6632.1994.tb38918.x.
An abnormal protease-resistant isoform of the protein PrP accumulates in the brain of hosts with transmissible spongiform encephalopathies (TSEs) and appears to be centrally involved in TSE pathogenesis. Studies with scrapie-infected tissue culture cells have indicated that this abnormal PrP is formed from an apparently normal precursor on the plasma membrane or along an endocytic pathway to the lysosomes. Inhibitors of protease-resistant PrP accumulation might serve as tools for studying the basic mechanism of protease-resistant PrP formation and as potential drugs for TSE therapy. Using scrapie-infected neuroblastoma cells to screen for such compounds in vitro, we found that the amyloid binding dye Congo red and certain sulfated glycans potently inhibited the accumulation of protease-resistant PrP in scrapie-infected cells without apparent effects on the metabolism of the normal isoform. The relative potencies of the sulfated glycans corresponded with their previously determined anti-scrapie activities in vivo, suggesting that the prophylactic effects of sulfated polyanions may be due to inhibition of protease-resistant PrP accumulation. Since protease-resistant PrP amyloid is known to contain sulfated glycosaminoglycans, as do other naturally derived amyloids, we hypothesize that these sulfated inhibitors competitively block binding between PrP and endogenous glycosaminoglycans that is important for its accumulation in a protease-resistant, potentially amyloidogenic state. Drugs which interfere with this (pre)amyloid-glycosaminoglycan interaction may be useful for treating a variety of amyloidoses.
在患有传染性海绵状脑病（TSE）的宿主大脑中，一种异常的、抗蛋白酶的蛋白质PrP异构体开始累积，并且似乎在TSE发病机制中起到核心作用。对感染羊瘙痒病的组织培养细胞的研究表明，这种异常的PrP是由质膜上或沿着通向溶酶体的内吞途径中的一种看似正常的前体形成的。抗蛋白酶PrP累积的抑制剂可能作为研究抗蛋白酶PrP形成基本机制的工具，以及作为TSE治疗的潜在药物。利用感染羊瘙痒病的神经母细胞瘤细胞在体外筛选此类化合物，我们发现淀粉样蛋白结合染料刚果红和某些硫酸化聚糖能有效抑制感染羊瘙痒病细胞中抗蛋白酶PrP的累积，而对正常异构体的代谢没有明显影响。硫酸化聚糖的相对效力与其先前在体内确定的抗羊瘙痒病活性相对应，这表明硫酸化聚阴离子的预防作用可能是由于抑制了抗蛋白酶PrP的累积。由于已知抗蛋白酶PrP淀粉样蛋白含有硫酸化糖胺聚糖，其他天然来源的淀粉样蛋白也是如此，我们推测这些硫酸化抑制剂竞争性地阻断PrP与内源性糖胺聚糖之间的结合，这种结合对于PrP在抗蛋白酶、潜在淀粉样生成状态下的累积很重要。干扰这种（前）淀粉样蛋白 - 糖胺聚糖相互作用的药物可能对治疗多种淀粉样变性病有用。
