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Two alternative pathways for generating transmissible prion disease de novo.
Natallia Makarava1,2, Regina Savtchenko3,4, Ilia V Baskakov5,6
1Center for Biomedical Engineering and Technology, University of Maryland School of Medicine, 111 S. Penn St., Baltimore, MD, 21201, USA. NMakarava@umaryland.edu.
Acta Neuropathologica Communications
|November 12, 2015
Summary
In vitro-generated atypical PrPres can cause prion disease, mimicking strains from recombinant PrP fibrils. This study models prion formation, showing atypical PrPres can initiate transmissible prion diseases in animals.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- Prion diseases can arise from in vitro-formed recombinant PrP (rPrP) fibrils, distinct from authentic prions (PrP(Sc)).
- A proposed mechanism involves two steps: rPrP fibrils forming atypical PrPres (a silent state), followed by atypical PrPres generating PrP(Sc) through rare templating events.
Purpose of the Study:
- To generate atypical PrPres in vitro and assess its capacity to induce prion disease.
- To compare the characteristics and disease-inducing potential of in vitro-generated atypical PrPres with brain-derived forms and rPrP fibrils.
Main Methods:
- In vitro generation of atypical PrPres.
- Inoculation of in vitro-generated atypical PrPres into animals.
- Analysis of prion formation, disease phenotypes, and PrP sialylation patterns.
Main Results:
- In vitro-generated atypical PrPres induced PrP(Sc) and prion disease with phenotypes similar to those from rPrP fibrils.
- Differences in sialylation between atypical PrPres and PrP(Sc) suggest distinct substrate recruitment.
- Atypical PrPres replicates slower than PrP(Sc), explaining PrP(Sc) competitive advantage.
Conclusions:
- Transmissible prion diseases with similar phenotypes can be generated by either rPrP fibrils or in vitro-produced atypical PrPres.
- Atypical PrPres preparations, even without PrP(Sc), can cause transmissible diseases in wild-type animals.
- In vitro-generated atypical PrPres serves as a valid model for brain-derived atypical PrPres.