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Prion isolate specified allotypic interactions between the cellular and scrapie prion proteins in congenic and
G A Carlson1, C Ebeling, S L Yang
1McLaughlin Research Institute, Great Falls, MT 59405.
Abstract:
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.
Insights
Prion strain diversity was investigated using mice with varying prion protein (PrP) gene alleles. Incubation times depend on PrP gene interactions, not just gene presence, influencing prion disease progression.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Prion diseases are characterized by diverse prion "strains" despite the absence of genetic material.
- The role of the prion protein (PrP) gene in determining prion strain characteristics and incubation times is not fully understood.
Purpose of the Study:
- To investigate the influence of different prion protein (PrP) gene alleles on prion strain diversity and incubation periods.
- To determine the genetic basis for variations in prion disease incubation times and neuropathology.
Main Methods:
- Inoculation of congenic and transgenic mice with varying numbers of PrP gene alleles (Prn-p(a) and Prn-pb) using three distinct prion strains (RML, 87V, 22A).
- Analysis of incubation times, prion protein (PrP) allotype levels (PrPC-A), and scrapie isoform of PrP (PrPSc) deposition patterns in mouse brains.
Main Results:
- Incubation time with RML prions was inversely related to the number of Prn-p(a) genes, linked to reduced PrPC-A substrate levels.
- Prn-p(a) extended incubation times for 87V and 22A strains, while Prn-pb was permissive.
- Distinct PrPSc accumulation patterns were observed for each prion isolate, suggesting a separate genetic locus influences neuropathology for the 87V strain.
Conclusions:
- Scrapie strain-specific incubation times can be attributed to the varying efficiency of allotypic interactions in converting PrPC to PrPSc.
- Prion protein gene interactions, rather than simply gene presence, significantly modulate prion disease incubation periods and outcomes.