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Protease-resistant prion protein produced in vitro lacks detectable infectivity
The Journal of General Virology
|February 6, 1999
Summary
Prion protein (PrP) conversion in vitro does not guarantee infectivity. Protease resistance acquisition by PrP(C) alone is insufficient for prion propagation, challenging the protein-only hypothesis.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- The 'protein-only' hypothesis posits infectious prions are misfolded prion proteins (PrPSc).
- PrPSc is distinguished from normal PrPC by protease resistance.
- In vitro conversion of PrPC to PrPSc has been achieved, but infectivity assays are complicated by excess PrPSc.
Purpose of the Study:
- To investigate if in vitro conversion of a specific mouse-human chimeric PrPC (MH2M PrPC) to protease-resistant MH2M PrPSc generates infectivity.
- To distinguish newly generated infectivity from the hamster PrPSc used in the conversion process.
Main Methods:
- Utilized transgenic mice expressing MH2M PrPC, which are susceptible to hamster scrapie.
- Attempted in vitro conversion of MH2M PrPC using hamster PrPSc.
- Assayed for infectivity using conventional mice to detect any pathogenic agent produced.
Main Results:
- Protease-resistant MH2M PrP was successfully produced in vitro.
- Bioassays in conventional mice did not detect any infectivity in the converted material.
Conclusions:
- The acquisition of protease resistance by PrP(C) in vitro is not sufficient for prion infectivity propagation.
- These findings challenge the sufficiency of the 'protein-only' hypothesis for prion replication.