Abstract
The physiological role of the cellular prion protein (PrPC) is incompletely understood. The expression of PrPC in hematopoietic stem cells and immune cells suggests a role in the development of these cells, and in PrPC knockout animals altered immune cell proliferation and phagocytic function have been observed. Recently, a spontaneous nonsense mutation at codon 32 in the PRNP gene in goats of the Norwegian Dairy breed was discovered, rendering homozygous animals devoid of PrPC. Here we report hematological and immunological analyses of homozygous goat kids lacking PrPC (PRNPTer/Ter) compared to heterozygous (PRNP+/Ter) and normal (PRNP+/+) kids. Levels of cell surface PrPC and PRNP mRNA in peripheral blood mononuclear cells (PBMCs) correlated well and were very low in PRNPTer/Ter, intermediate in PRNP+/Ter and high in PRNP+/+ kids. The PRNPTer/Ter animals had a shift in blood cell composition with an elevated number of red blood cells (RBCs) and a tendency toward a smaller mean RBC volume (P = 0.08) and an increased number of neutrophils (P = 0.068), all values within the reference ranges. Morphological investigations of blood smears and bone marrow imprints did not reveal irregularities. Studies of relative composition of PBMCs, phagocytic ability of monocytes and T-cell proliferation revealed no significant differences between the genotypes. Our data suggest that PrPC has a role in bone marrow physiology and warrant further studies of PrPC in erythroid and immune cell progenitors as well as differentiated effector cells also under stressful conditions. Altogether, this genetically unmanipulated PrPC-free animal model represents a unique opportunity to unveil the enigmatic physiology and function of PrPC.
Highlights
The cellular prion protein (PrPC) was first described as the substrate for PrP scrapie (PrPSc) (Prusiner, 1982; Brandner et al, 1996a,b), a misfolded and aggregation-prone form of the protein detected in brain tissue of animals diagnosed with transmissible spongiform encephalopathies, often called prion diseases
Expression of PrPC in Leukocytes Correlates with Genotype The absence of PrPC on peripheral blood mononuclear cells (PBMCs) from PRNPTer/Ter goats was confirmed by three different anti-PrPC monoclonal antibodies (mAbs) (Figure 1A and data not shown)
Anti-PrPC mAbs staining of whole blood revealed that PrPC was not expressed on the surface of granulocytes in goats of either genotype, while its presence was confirmed in the lymphocyte gate in PRNP+/+ goats (Figure 1B)
Summary
The cellular prion protein (PrPC) was first described as the substrate for PrP scrapie (PrPSc) (Prusiner, 1982; Brandner et al, 1996a,b), a misfolded and aggregation-prone form of the protein detected in brain tissue of animals diagnosed with transmissible spongiform encephalopathies, often called prion diseases. These are fatal neurodegenerative diseases occurring naturally in humans and ruminants and include Creutzfeldt-Jakob disease, bovine spongiform encephalopathy, scrapie, and chronic wasting disease. PrPC is expressed in long-term hematopoietic stem cells (Dodelet and Cashman, 1998; Zhang et al, 2006) and may contribute to maintenance of stem cell properties, since bone marrow stem cells derived from PrPC
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