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Regional heterogeneity of cellular prion protein isoforms in the mouse brain
Vincent Beringue1, Gary Mallinson, Maria Kaisar
1CNS Infection and Immunity Group, and Department of Neurogenetics, Imperial College, Norfolk Place, London W2 1PG, UK.
Abstract:
Prion diseases are a group of invariably fatal neurodegenerative disorders that include Creutzfeldt-Jakob disease in humans, scrapie in sheep and goats, and bovine spongiform encephalopathy in cattle. The infectious agent or prion is largely composed of an abnormal isoform (PrPSc) of a host encoded normal cellular protein (PrPc). The conversion of PrPc to PrPSc is a dynamic process and, for reasons that are not clear, the distribution of spongiform change and PrPSc deposition varies among prion strains. An obvious explanation for this would be that the transformation efficiency in any given brain region depends on favourable interactions between conformations of PrPc and the prion strain being propagated within it. However, identification of specific PrPc conformations has until now been hampered by a lack of suitable panels of antibodies that discriminate PrPc subspecies under native conditions. In this study, we show that monoclonal antibodies raised against recombinant human prion protein folded into alpha or beta conformations exhibit striking heterogeneity in their specificity for truncations and glycoforms of mouse brain PrPc. We then show that some of these PrPc isoforms are expressed differentially in certain mouse brain regions. This suggests that variation in the expression of PrPc conformations in different brain regions may dictate the pattern of PrPSc deposition and vacuolation, characteristic for different prion strains.
Insights
Prion diseases, like CJD, stem from abnormal prion protein (PrPSc) converting normal forms (PrPc). This study reveals regional PrPc conformation variations may explain strain-specific disease patterns in the brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Biochemistry
Background:
- Prion diseases are fatal neurodegenerative conditions caused by misfolded prion proteins (PrPSc).
- The distribution of prion-induced damage varies between prion strains, but the underlying reasons are unclear.
- Identifying specific prion protein (PrPc) conformations has been challenging due to a lack of suitable antibodies.
Purpose of the Study:
- To investigate whether regional differences in prion protein (PrPc) conformations influence the characteristic patterns of prion disease pathology.
- To develop and utilize novel monoclonal antibodies to differentiate PrPc conformations in native brain tissue.
Main Methods:
- Generated monoclonal antibodies against alpha- and beta-folded recombinant human prion protein.
- Tested antibody specificity against mouse brain PrPc truncations and glycoforms.
- Assessed differential expression of PrPc isoforms in various mouse brain regions.
Main Results:
- Monoclonal antibodies showed varied specificity for different PrPc truncations and glycoforms.
- Certain PrPc isoforms were found to be differentially expressed across distinct brain regions.
- This differential expression suggests a potential mechanism for strain-specific pathology.
Conclusions:
- Regional variations in PrPc conformation expression may determine the specific patterns of PrPSc deposition and spongiform change observed in different prion strains.
- This finding provides a potential explanation for the heterogeneity of prion disease pathology.