Carlson G A, Ebeling C, Yang S L, Telling G, Torchia M, Groth D, Westaway D, DeArmond S J, Prusiner S B
McLaughlin Research Institute, Great Falls, MT 59405.
Proc Natl Acad Sci U S A. 1994 Jun 7;91(12):5690-4. doi: 10.1073/pnas.91.12.5690.
Different prion isolates, often referred to as "strains," present an enigma because considerable evidence argues that prions are devoid of nucleic acid. To investigate prion diversity, we inoculated three "strains" of prions into congenic and transgenic mice harboring variable numbers of two different alleles, designated a and b, of the prion protein (PrP) structural gene, Prn-p. The length of the incubation time was inversely related to the number of Prn-p(a) genes in mice inoculated with the Rocky Mountain Laboratory (RML) prion strain. Results with mice lacking this locus (Prn-p0/0) and transgenic mice argue that long incubation times are not a dominant trait as thought for many years, but rather they are due to reduced levels of the substrate PrPC-A (cellular isoform of PrP, allotype A) in (Prn-p(a) x Prn-pb)F1 mice. In contrast, the Prn-p(a) gene extended incubation times in mice inoculated with the 87V and 22A prion strains, whereas the Prn-pb gene was permissive. Experiments with the 87V isolate suggest that a genetic locus distinct from Prn-p controls deposition of the scrapie isoform of PrP (PrPSc) and attendant neuropathology. Each prion isolate produced distinguishable patterns of PrPSc accumulation in brain; of note, the patterns in Prn-p(a) and Prn-pb congenic mice inoculated with RML prions were more different than those in congenic Prn-pb mice with RML or 22A prions. Our results suggest that scrapie "strain-specific" incubation times can be explained by differences in the relative efficiency of allotypic interactions that lead to conversion of PrPC into PrPSc.
不同的朊病毒毒株，通常被称为“菌株”，呈现出一个谜团，因为大量证据表明朊病毒不含核酸。为了研究朊病毒的多样性，我们将三种“菌株”的朊病毒接种到携带朊病毒蛋白（PrP）结构基因Prn-p的两个不同等位基因（分别命名为a和b）数量可变的同基因和转基因小鼠体内。潜伏期的长短与接种落基山实验室（RML）朊病毒毒株的小鼠体内Prn-p(a)基因的数量呈负相关。对缺乏该基因座（Prn-p0/0）的小鼠和转基因小鼠的研究结果表明，长时间的潜伏期并非如多年来所认为的那样是一种显性性状，而是由于（Prn-p(a)×Prn-pb）F1小鼠体内底物PrPC-A（PrP的细胞异构体，同种异型A）水平降低所致。相比之下，Prn-p(a)基因延长了接种87V和22A朊病毒毒株的小鼠的潜伏期，而Prn-pb基因则没有这种作用。对87V毒株的实验表明，一个与Prn-p不同的基因座控制着PrP的瘙痒病异构体（PrPSc）的沉积及相关神经病理学变化。每种朊病毒毒株在大脑中产生了可区分的PrPSc积累模式；值得注意的是，接种RML朊病毒的Prn-p(a)和Prn-pb同基因小鼠中的模式比接种RML或22A朊病毒的Prn-pb同基因小鼠中的模式差异更大。我们的结果表明，瘙痒病“菌株特异性”潜伏期可以通过导致PrPC转化为PrPSc的同种异型相互作用的相对效率差异来解释。
