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Assessing Transmissible Spongiform Encephalopathy Species Barriers with an In Vitro Prion Protein Conversion Assay
Published on: March 10, 2015
Small ruminant nor98 prions share biochemical features with human gerstmann-sträussler-scheinker disease and variably
Laura Pirisinu1, Romolo Nonno, Elena Esposito
1Department of Veterinary Public Health and Food Safety, Istituto Superiore di Sanità, Rome, Italy. laura.pirisinu@iss.it
Abstract:
Prion diseases are classically characterized by the accumulation of pathological prion protein (PrP(Sc)) with the protease resistant C-terminal fragment (PrP(res)) of 27-30 kDa. However, in both humans and animals, prion diseases with atypical biochemical features, characterized by PK-resistant PrP internal fragments (PrP(res)) cleaved at both the N and C termini, have been described. In this study we performed a detailed comparison of the biochemical features of PrP(Sc) from atypical prion diseases including human Gerstmann-Sträussler-Scheinker disease (GSS) and variably protease-sensitive prionopathy (VPSPr) and in small ruminant Nor98 or atypical scrapie. The kinetics of PrP(res) production and its cleavage sites after PK digestion were analyzed, along with the PrP(Sc) conformational stability, using a new method able to characterize both protease-resistant and protease-sensitive PrP(Sc) components. All these PrP(Sc) types shared common and distinctive biochemical features compared to PrP(Sc) from classical prion diseases such as sporadic Creutzfeldt-Jakob disease and scrapie. Notwithstanding, distinct biochemical signatures based on PrP(res) cleavage sites and PrP(Sc) conformational stability were identified in GSS A117V, GSS F198S, GSS P102L and VPSPr, which allowed their specific identification. Importantly, the biochemical properties of PrP(Sc) from Nor98 and GSS P102L largely overlapped, but were distinct from the other human prions investigated. Finally, our study paves the way towards more refined comparative approaches to the characterization of prions at the animal-human interface.
Insights
This study reveals distinct biochemical signatures for atypical prion diseases, differentiating human Gerstmann-Sträussler-Scheinker disease and variably protease-sensitive prionopathy from classical forms. These findings enhance prion characterization at the animal-human interface.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Prion diseases involve pathological prion protein (PrP(Sc)) accumulation.
- Atypical prion diseases exhibit unique biochemical features, including internal protease-resistant PrP fragments (PrP(res)).
Purpose of the Study:
- To compare the biochemical characteristics of PrP(Sc) in various atypical prion diseases.
- To identify distinct molecular signatures for specific human and animal prion strains.
Main Methods:
- Detailed analysis of PrP(res) production kinetics and cleavage sites after proteinase K (PK) digestion.
- Assessment of PrP(Sc) conformational stability using a novel method for protease-resistant and sensitive components.
Main Results:
- Atypical prion diseases share common yet distinct biochemical features compared to classical prion diseases.
- Specific biochemical signatures were identified for GSS A117V, GSS F198S, GSS P102L, and VPSPr based on PrP(res) cleavage and conformational stability.
- PrP(Sc) from Nor98 (animal) and GSS P102L (human) showed overlapping biochemical properties, distinct from other human prions.
Conclusions:
- Distinct biochemical signatures allow for the specific identification of atypical prion diseases.
- Biochemical characterization provides a refined approach for understanding prions at the animal-human interface.
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