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Updated: Jun 20, 2026
Protein Misfolding Cyclic Amplification of Prions
Published on: November 7, 2012
Propagation of PrPSc in mice reveals impact of aggregate composition on prion disease pathogenesis
Sheng Chun Chang1,2, Samia Hannaoui1,2, Maria Immaculata Arifin1,2
1Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada.
Abstract:
Infectious prions consist of PrPSc, a misfolded, aggregation-prone isoform of the host's prion protein. PrPSc assemblies encode distinct biochemical and biological properties. They harbor a specific profile of PrPSc species, from small oligomers to fibrils in different ratios, where the highest infectivity aligns with oligomeric particles. To investigate the impact of PrPSc aggregate complexity on prion propagation, biochemical properties, and disease pathogenesis, we fractionated elk prions by sedimentation velocity centrifugation, followed by sub-passages of individual fractions in cervidized mice. Upon first passage, different fractions generated PrPSc with distinct biochemical, biophysical, and neuropathological profiles. Notably, low or high molecular weight PrPSc aggregates caused different clinical signs of hyperexcitability or lethargy, respectively, which were retained over passage, whereas other properties converged. Our findings suggest that PrPSc quaternary structure determines an initial selection of a specific replication environment, resulting in transmissible features that are independent of PrPSc biochemical and biophysical properties.
Insights
Prion aggregate structure influences disease, with distinct sizes causing varied symptoms. This complex quaternary structure dictates prion replication and transmission, independent of biochemical traits.
Area of Science:
- Neuroscience
- Biochemistry
- Infectious Diseases
Background:
- Infectious prions are misfolded prion protein (PrPSc) aggregates.
- PrPSc assemblies exhibit diverse biochemical and biological properties.
- Aggregate composition, including oligomers and fibrils, correlates with infectivity.
Purpose of the Study:
- To investigate how PrPSc aggregate complexity affects prion propagation.
- To determine the impact of aggregate structure on biochemical properties and disease pathogenesis.
- To understand the role of PrPSc quaternary structure in prion infectivity.
Main Methods:
- Fractionation of elk prions using sedimentation velocity centrifugation.
- Sub-passage of individual PrPSc fractions in cervidized mice.
- Analysis of biochemical, biophysical, and neuropathological profiles of PrPSc species.
Main Results:
- Different PrPSc fractions generated distinct PrPSc profiles upon first passage.
- Low and high molecular weight aggregates induced specific clinical signs (hyperexcitability and lethargy, respectively).
- These distinct clinical signs were retained across passages, while other properties converged.
Conclusions:
- PrPSc quaternary structure dictates the initial replication environment.
- This structural influence leads to transmissible features independent of PrPSc biochemical properties.
- Aggregate complexity plays a critical role in prion disease pathogenesis and transmission dynamics.
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