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The molecular pathology of scrapie and the biological basis of lesion targeting
H Fraser1, M E Bruce, P A McBride
1AFRC & MRC Neuropathogenesis Unit, Edinburgh.
Abstract:
Strains of scrapie virus can only be distinguished from the incubation period and neuropathology of the disease they induce in mice of different Sinc genotypes. There are two main aspects of the neuropathology: a spongiosis or degenerative vacuolation associated with the replication of virus, and cerebral amyloid plaques. The relationship between these two is unclear - they can occupy topographically quite different centres in the CNS and the timing of their occurrence is different. Surprisingly this is also the case using the very precise targeting provided by the intraocular infection route. Here the earliest spongiosis is very localised into the primary and secondary projections from the retina, but plaques, when they occur, occupy quite different sites. The relationship between plaques and spongy degeneration is probably a neuroanatomical one, similar to that suggested between plaques and tangle-bearing neurons in Alzheimer's disease. A third aspect of the pathology is the occurrence of SAF in negative-stained E.M. preparations, formed from the aggregation of a sialoglycoprotein called PrP or SAF-protein. Immunolabelling of plaques with antisera to SAF protein shows as yet that there is no antigenic variation in the protein prepared from different scrapie models with different strains of the virus based on available reagents. Strain variation is only recognised on biological criteria; as yet, there are no independent molecular markers or in vitro tests which can account for the biological variation.
Insights
Scrapie virus strains are distinguished by incubation period and neuropathology in mice. Current molecular markers do not explain biological strain variation, highlighting the need for further research.
Area of Science:
- Neuroscience
- Virology
- Pathology
Background:
- Scrapie virus strains are differentiated by incubation period and neuropathology in mice with different Sinc genotypes.
- Neuropathology involves spongiosis (degenerative vacuolation) and cerebral amyloid plaques, with unclear topographical and temporal relationships.
- Scrapie-associated fibrils (SAF) are formed from the aggregation of PrP (SAF-protein).
Purpose of the Study:
- To investigate the relationship between spongiosis and amyloid plaques in scrapie neuropathology.
- To explore potential molecular markers for scrapie strain variation.
- To understand the role of PrP in scrapie pathogenesis.
Main Methods:
- Infection of mice with different Sinc genotypes.
- Intraocular infection route for precise targeting.
- Neuropathological examination including spongiosis and plaque assessment.
- Immunolabelling of plaques with antisera to SAF protein.
- Electron microscopy for SAF detection.
Main Results:
- Spongiosis and plaques exhibit different topographical distributions and timing, even with intraocular infection.
- Plaque-and-spongiosis relationship may be neuroanatomical, similar to Alzheimer's disease.
- Immunolabelling shows no antigenic variation in PrP from different scrapie models.
- Strain variation is currently only recognized by biological criteria.
Conclusions:
- The relationship between spongiosis and amyloid plaques in scrapie is likely neuroanatomical.
- No independent molecular markers or in vitro tests currently explain scrapie strain variation.
- Further research is needed to identify molecular correlates of scrapie strain diversity.