Carlson G A, Westaway D, DeArmond S J, Peterson-Torchia M, Prusiner S B
McLaughlin Research Institute, Great Falls, MT 59401.
Proc Natl Acad Sci U S A. 1989 Oct;86(19):7475-9. doi: 10.1073/pnas.86.19.7475.
Scrapie is an infectious neurodegenerative disease caused by unusual pathogens called prions, in which no scrapie-specific nucleic acid has been detected to date. The only known component of the prion is the scrapie isoform of prion protein (PrPSc), which is encoded by a host gene (Prn-p). Isolates of scrapie agent were prepared by passage of infectivity through inbred strains of mice that differ in scrapie incubation time and produce PrPSc molecules differing by two amino acids. Both the length and variability of the incubation period were increased by inocula containing allogeneic PrPSc. For example, Prn-pb I/Ln mice inoculated with scrapie isolate passaged through Prn-pa NZW mice had incubation times of 283 +/- 21 days compared with a 193 +/- 6 day incubation time seen with isolate passaged once through isologous I/Ln mice. No further shortening of incubation time was observed following further isologous passage. NZW incubation times were prolonged by inoculation with prions from I/Ln mice. Results from (NZW x I/Ln)F2 mice and from using inocula from donors isologous for Prn-p but otherwise allogeneic with respect to the recipient suggest that the primary structure of PrPSc is responsible for these incubation time results. Incubation times in (NZW x I/Ln)F1 mice were constant regardless of the passage histories of the scrapie isolates and were equivalent to those of I/Ln mice inoculated with I/Ln prions, contending that prolongation of scrapie incubation time by the prion incubation time gene Prn-i is fully dominant. I/Ln incubation times longer than those in F1 hybrids may reflect a reduced efficiency of allogeneic PrPSc in initiating disease. Although some investigators propose that differences in behavior among scrapie isolates reflect host selection and argue for a nucleic acid genome, we suggest that the variation observed among our scrapie isolates is epigenetic, reflecting host-directed differences in the amino acid sequence of PrPSc.
羊瘙痒症是一种由称为朊病毒的异常病原体引起的传染性神经退行性疾病，迄今为止尚未检测到羊瘙痒症特异性核酸。朊病毒唯一已知的成分是朊病毒蛋白（PrPSc）的羊瘙痒症异构体，它由宿主基因（Prn-p）编码。通过将感染性物质接种到近交系小鼠中制备羊瘙痒症病原体分离株，这些小鼠的羊瘙痒症潜伏期不同，产生的PrPSc分子在两个氨基酸上存在差异。含有异源PrPSc的接种物会增加潜伏期的长度和变异性。例如，接种经过Prn-pa NZW小鼠传代的羊瘙痒症分离株的Prn-pb I/Ln小鼠，其潜伏期为283±21天，而接种经过同基因I/Ln小鼠传代一次的分离株的潜伏期为193±6天。同基因进一步传代后未观察到潜伏期进一步缩短。接种来自I/Ln小鼠的朊病毒会延长NZW小鼠的潜伏期。（NZW×I/Ln）F2小鼠以及使用与Prn-p同基因但在其他方面与受体异源的供体接种物的实验结果表明，PrPSc的一级结构是这些潜伏期结果的原因。（NZW×I/Ln）F1小鼠的潜伏期是恒定的，与羊瘙痒症分离株的传代历史无关，并且与接种I/Ln朊病毒的I/Ln小鼠的潜伏期相同，这表明朊病毒潜伏期基因Prn-i对羊瘙痒症潜伏期延长具有完全显性作用。I/Ln小鼠的潜伏期比F1杂种小鼠长，这可能反映了异源PrPSc引发疾病的效率降低。尽管一些研究人员提出羊瘙痒症分离株之间行为的差异反映了宿主选择，并主张存在核酸基因组，但我们认为我们观察到的羊瘙痒症分离株之间的差异是表观遗传的，反映了宿主对PrPSc氨基酸序列的定向差异。
