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Infection-specific prion protein (PrP) accumulates on neuronal plasmalemma in scrapie-infected mice
M Jeffrey1, C M Goodsir, M E Bruce
1Lasswade Veterinary Laboratory, Penicuik, Midlothian, United Kingdom.
Abstract:
Prion protein (PrP) is an abundant membrane-associated host protein which accumulates in abnormal, relatively protease-resistant forms in the brains of animals with scrapie and related diseases. Using correlative light and electron microscopy we determined the sites of subcellular localization of PrP in mice infected with the 87V strain of scrapie. Disease-specific accumulation of PrP was observed at light microscopy as amyloid plaques or as diffuse or granular staining within the neuropil, often clearly associated with individual neurons. Serial electron microscopical preparations were immunostained for PrP by the immunogold method. Gold particles were located on amyloid fibrils and on the plasmalemma of neurites at the periphery of plaques and in the neuropil, irrespective of the morphological form of PrP accumulation when viewed by light microscopy. This suggests the amyloid fibrils are formed following the accumulation and aggregation of sub-unit proteins at the plasmalemma and, furthermore, that normal PrP may be converted to its pathological form at this site.
Insights
Abnormal prion protein (PrP) accumulates in the brain during scrapie infection. This study reveals PrP aggregation occurs at the neuronal cell membrane, suggesting this is where the conversion to pathological forms begins.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Prion protein (PrP) is a host protein found on cell membranes.
- Abnormal PrP accumulation is characteristic of prion diseases like scrapie.
- The precise subcellular sites of PrP conversion and aggregation remain unclear.
Purpose of the Study:
- To determine the subcellular localization of abnormal prion protein (PrP) in scrapie-infected mouse brains.
- To investigate the relationship between different morphological forms of PrP accumulation and their sites of occurrence.
- To elucidate the initial steps of pathological PrP formation.
Main Methods:
- Correlative light and electron microscopy (CLEM) was employed.
- Immunogold labeling was used to detect PrP at the ultrastructural level.
- Scrapie-infected mouse brains (87V strain) were analyzed.
Main Results:
- Disease-specific PrP accumulation was observed as amyloid plaques and diffuse/granular staining in the neuropil.
- Electron microscopy showed gold particles localized to amyloid fibrils and the plasmalemma of neurites.
- PrP deposition was found at the periphery of plaques and within the neuropil, regardless of light microscopic appearance.
Conclusions:
- Amyloid fibrils appear to form from subunit protein accumulation and aggregation at the plasmalemma.
- The neuronal cell membrane (plasmalemma) is a key site for pathological PrP formation.
- Normal PrP may be converted to its abnormal, disease-associated form at the cell surface.