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Murine scrapie-infected neurons in vivo release excess prion protein into the extracellular space
M Jeffrey1, C M Goodsir, M E Bruce
1Lasswade Veterinary Laboratory, Midlothian, Scotland, UK.
Abstract:
An originally heretical proposition that the transmissible spongiform encephalopathies are caused by a host-coded protein (the prion hypothesis) is now current dogma. Indeed these disorders are commonly called prion diseases but the prion hypothesis provides no readily acceptable explanation for the source of the informational component of the agent necessary to code for the diversity of strains of scrapie. Ultrastructural immunolocalisation of prion protein (PrP) in murine scrapie shows that PrP accumulates in association with the plasmalemma of neurones, diffusing from the neuronal cell surface into the extracellular space around small neurites prior to aggregation and fibril assembly. These events occur without the involvement of other cell types. The area of neuropil infiltrated with extracellular PrP around infected neurons and neurites indicates that the form of PrP initially produced is not immediately amyloidogenic.
Insights
Transmissible spongiform encephalopathies are linked to prion protein (PrP) accumulation. In murine scrapie, PrP originates from neurons and infiltrates extracellular spaces before forming fibrils.
Area of Science:
- Neuroscience
- Protein Biochemistry
- Infectious Diseases
Background:
- The prion hypothesis posits transmissible spongiform encephalopathies (TSEs) stem from a host-coded protein, now widely accepted.
- However, the prion hypothesis lacks a clear explanation for the informational component driving scrapie strain diversity.
Purpose of the Study:
- To investigate the cellular origin and early aggregation process of prion protein (PrP) in murine scrapie.
- To determine if extracellular PrP accumulation precedes fibril formation and amyloidogenesis.
Main Methods:
- Ultrastructural immunolocalization of prion protein (PrP) in the brains of mice infected with scrapie.
Main Results:
- PrP was observed to accumulate on the neuronal plasmalemma in murine scrapie.
- PrP diffused from the neuronal cell surface into the extracellular space around neurites.
- Extracellular PrP infiltration occurred before aggregation and fibril assembly, without involving other cell types.
Conclusions:
- Neuronal cell surface is the primary site for initial prion protein (PrP) production in scrapie.
- Early extracellular PrP accumulation is not immediately amyloidogenic, suggesting a distinct early-stage mechanism in prion disease pathogenesis.