|Knowles, Donald - Don|
Submitted to: NeuroReport
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 1/12/2006
Publication Date: 2/6/2006
Citation: Hoesing, L.M., Baszler, T.V., O'Rourke, K.I., Suarez, C.E., Bakko, M., Alverson, J., Knowles, Jr., D.P. 2006. Fewer PrPc myeloid-based cells in sheep with the prion resistant genotype. NeuroReport. 17(2):125-129. Interpretive Summary: Scrapie is part of a group of neurodegenerative diseases called transmissible spongiform encephalopathies (TSE’s) or prion diseases. Numerous sheep with genes that encode prion protein form 171QQ have developed scrapie. Only a handful of sheep with genes that encode form 171RR have developed scrapie. One reason for this disease difference between sheep of different prion genetics could be due to differences in expression levels of the prion protein on the surface of monocytes and microglia cell types. Monocytes differentiate to macrophages and microglia, and both of these differentiated cell types accumulate prion in susceptible sheep. This study showed that there were fewer prion protein molecules on microglia and monocytes in sheep with the 171RR form than in sheep with the 171QQ form. This suggests that the amount of prion protein on these cell types regulates prion accumulation in sheep.
Technical Abstract: Background and Objectives. Scrapie, a prion disease of sheep, is characterized by the conversion of a normal, cellular prion protein (PrPc) to an abnormal partially protease-resistant prion protein (PrPSc). The sheep prion gene (PRNP) that encodes PrPc is a determinant and a predictor of prion disease. Whereas there have been numerous sheep with PRNP genetics that encode for 171QQ that develop scrapie, there have been relatively few cases of sheep with PRNP genetics that encode for 171RR with scrapie disease. Since microglia and macrophages accumulate PrPSc in scrapie-infected sheep, we examined microglia, resident brain tissue macrophages, and peripheral blood monocytes, a precursor of macrophages, for differences in cell surface PrPc expression between sheep with 171QQ, 171QR, or 171RR PRNP genetics. Design and Methods. Microglia and peripheral blood mononuclear cells (PBMC) were isolated from sheep with the PRNP diploid genetics of AA136RR154QQ171, AA136RR154QR171 and AA136RR154RR171. Cells were examined for the presence of cell surface PrPc and various cell surface markers using immunocytochemistry and analyzed using flow cytometric analysis. Results. There were statistically (±1 standard deviation) decreased numbers of PrPc positive microglia and CD14 positive monocytes from sheep with 171RR PRNP genetics than from sheep with either 171QR or 171QQ PRNP genetics. In addition, by using the difference in mean fluorescence intensity (MFI), less PrPc molecules on the cell surface of immortalized microglia and CD14 positive monocytes were observed from sheep with 171RR PRNP genetics than from sheep with either 171QR or 171QQ PRNP genetics. Interpretation and Conclusions. One possibility for the lack of PrPSc accumulation in brains and lymph nodes of scrapie-exposed sheep with 171RR PRNP genetics is due to fewer PrPc positive cells or less PrPc on the surface of myeloid-derived cells available for conversion of PrPc to PrPSc.