Caughey B
Laboratory of Persistent Viral Diseases, NIH Rocky Mountain Laboratories, National Institute for Allergy and Infectious Diseases, Hamilton, Montana 59840.
Philos Trans R Soc Lond B Biol Sci. 1994 Mar 29;343(1306):399-404. doi: 10.1098/rstb.1994.0035.
An abnormally protease-resistant and apparently neuropathogenic form of PrP accumulates in the brains of hosts with scrapie and related transmissible spongiform encephalopathies. Studies with scrapie-infected neuroblastoma cells have highlighted dramatic differences in the metabolism of the normal (protease-sensitive) and scrapie-associated (protease-resistant) isoforms of PrP. Furthermore, this model has been useful in identifying inhibitors of protease-resistant PrP accumulation and scrapie agent replication which are valuable as potential therapeutic agents and as probes of the mechanism of protease-resistant PrP formation. These inhibitors include the amyloid stain Congo red and certain sulphated glycans which are glycosaminoglycans themselves or glycosaminoglycan analogues. The relative potencies of various sulphated glycans correlate with their previously determined anti-scrapie activities in vivo, suggesting that the prophylactic effects of sulphated polyanions is due to inhibition of protease-resistant PrP accumulation. These and other observations suggest that an interaction of PrP with endogenous sulphated glycosaminoglycans or proteoglycans is important in protease-resistant PrP accumulation, and raise the possibility that therapies for transmissible spongiform encephalopathies and other amyloidoses could be based on blocking (pre)amyloid-glycosaminoglycan interactions.
在患有羊瘙痒症及相关传染性海绵状脑病的宿主大脑中，一种异常的、抗蛋白酶且明显具有神经致病性的朊蛋白（PrP）形式会累积。对感染羊瘙痒症的神经母细胞瘤细胞的研究突出了正常（蛋白酶敏感）和羊瘙痒症相关（蛋白酶抗性）PrP异构体在代谢上的显著差异。此外，该模型在鉴定抗蛋白酶抗性PrP累积和羊瘙痒症病原体复制的抑制剂方面很有用，这些抑制剂作为潜在治疗剂以及蛋白酶抗性PrP形成机制的探针具有重要价值。这些抑制剂包括淀粉样染色剂刚果红和某些硫酸化聚糖，它们本身是糖胺聚糖或糖胺聚糖类似物。各种硫酸化聚糖的相对效力与其先前确定的体内抗羊瘙痒症活性相关，这表明硫酸化聚阴离子的预防作用是由于抑制了蛋白酶抗性PrP的累积。这些及其他观察结果表明，PrP与内源性硫酸化糖胺聚糖或蛋白聚糖的相互作用在蛋白酶抗性PrP累积中很重要，并增加了这样一种可能性，即针对传染性海绵状脑病和其他淀粉样变性的治疗可能基于阻断（前）淀粉样蛋白 - 糖胺聚糖相互作用。
