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Mutant knock-in mice display enhanced susceptibility to pure prion protein fibrils
Daniel J Walsh1, Heidi Standke2, Allison Kraus2
1Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire 03755, USA.
Abstract:
Prion diseases manifest clinically in three different forms. Sporadic and infectious forms of prion disease are caused by the conversion of WT, cellular prion protein (PrPC) into its pathogenic conformer (PrPSc). In contrast, genetic forms of prion diseases are caused by mutations in the PrP sequence that promote mutant PrPSc formation. When reconstituted with either polyanionic or lipid cofactors, purified PrPC substrate can be converted in vitro into PrPSc products that display high levels of specific infectivity when inoculated in WT hosts. In contrast, various protein-only PrPSc molecules formed in the absence of cofactors display much lower levels of specific infectivity. Here, we report that protein-only PrPSc molecules with different sequences can induce the formation of proteinase K-resistant PrPSc molecules and spongiform degeneration in the brains of knock-in mice expressing PrP harbouring the pathogenic E200K mutation, but not in hosts expressing WT PrP. These results indicate that the E200K mutation enhances host susceptibility to various protein-only PrPSc fibrils, suggesting fundamental differences in the replication mechanisms of WT versus mutant prions.
Insights
Prion diseases, including genetic forms, show varied susceptibility to different prion strains. The E200K mutation in prion protein enhances host susceptibility to protein-only prion fibrils.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Prion diseases are fatal neurodegenerative disorders.
- Prion protein (PrP) misfolding and aggregation cause disease.
- Genetic, sporadic, and infectious forms exist, differing in etiology.
Purpose of the Study:
- Investigate the influence of the E200K mutation on prion disease susceptibility.
- Compare the infectivity of protein-only prions in WT versus E200K mutant PrP models.
- Elucidate differences in prion replication mechanisms.
Main Methods:
- Utilized knock-in mouse models expressing WT or E200K mutant PrP.
- Inoculated mice with various protein-only PrPSc fibrils.
- Assessed PrPSc formation and spongiform degeneration in brains.
Main Results:
- Protein-only PrPSc fibrils induced PrPSc formation and spongiform degeneration in E200K mutant mice.
- No induction of disease was observed in WT PrP mice.
- E200K mutation significantly enhanced host susceptibility to diverse protein-only PrPSc strains.
Conclusions:
- The E200K mutation confers heightened susceptibility to specific protein-only prion strains.
- Suggests distinct prion replication pathways for WT and mutant prions.
- Highlights the role of PrP sequence in determining prion strain interactions.
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