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Heterologous PrP molecules interfere with accumulation of protease-resistant PrP in scrapie-infected murine
S A Priola1, B Caughey, R E Race
1Laboratory of Persistent Viral Diseases, National Institute of Allergy and Infectious Diseases, Rocky Mountain Laboratories, Hamilton, Montana 59840.
Abstract:
Mutations within a host cellular protein, PrP, have been associated with disease in the transmissible spongiform encephalopathies. Murine neuroblastoma cells persistently infected with mouse scrapie accumulate protease-resistant PrP (PrP-res), the abnormal form of PrP associated with disease in the transmissible spongiform encephalopathies. These cells provide a controlled system in which to study the molecular interactions which are important in the formation of PrP-res. We have expressed recombinant PrP molecules in mouse scrapie-infected murine neuroblastoma cells and assayed the effect of these heterologous PrP genes on the formation and accumulation of PrP-res. The results demonstrate that expression of heterologous PrP molecules which differ from the endogenous PrP by as little as one amino acid can profoundly interfere with the overall accumulation of PrP-res. The data suggest that precise interactions between homologous PrP molecules are important in PrP-res accumulation and that heterologous PrP molecules can block these interactions.
Insights
Prion protein (PrP) interactions are key in transmissible spongiform encephalopathies. Introducing altered PrP molecules into infected cells disrupts the accumulation of disease-associated PrP-res, suggesting specific PrP interactions are crucial for disease progression.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Transmissible spongiform encephalopathies (TSEs) are linked to mutations in the host prion protein (PrP).
- Scrapie-infected neuroblastoma cells accumulate abnormal PrP (PrP-res), serving as a model for studying TSE molecular mechanisms.
Purpose of the Study:
- To investigate the impact of heterologous prion protein (PrP) expression on PrP-res accumulation in scrapie-infected cells.
- To elucidate the role of specific PrP molecule interactions in the formation of disease-associated PrP-res.
Main Methods:
- Expression of recombinant PrP molecules in mouse scrapie-infected murine neuroblastoma cells.
- Assaying the effect of these heterologous PrP genes on PrP-res formation and accumulation.
Main Results:
- Expression of heterologous PrP molecules, even with a single amino acid difference, significantly interfered with PrP-res accumulation.
- These findings indicate that PrP-res accumulation is sensitive to the precise nature of PrP interactions.
Conclusions:
- Homologous PrP interactions are critical for the accumulation of PrP-res.
- Heterologous PrP molecules can act as inhibitors by blocking essential homologous PrP interactions, offering insights into TSE pathogenesis.