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Published on: May 23, 2025
Activated platelets of patients with paroxysmal nocturnal hemoglobinuria express cellular prion protein
Karel Holada1, Jan Simak, Antonio M Risitano
1Laboratory of Cellular Hematology, Division of Hematology, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, USA.
Abstract:
Cellular prion protein (PrPc) is a glycosylphosphatidylinositol (GPI)-anchored membrane glycoprotein that contains a putative membrane-spanning section. Patients with paroxysmal nocturnal hemoglobinuria (PNH) lack GPI proteins on the surface of somatically mutated hematopoietic stem cell and its progeny. Platelet expression of PrPc was studied in 8 PNH patients. Resting PNH (CD55(-)) platelets were devoid of surface PrPc, but activation of platelets resulted in the surface expression of PrPc. Expressed PrPc was detected by 2 monoclonal antibodies (mAbs) against the N-terminal part of the molecule but not by mAb 6H4, which binds at the C-terminus beyond the membrane-spanning section. However, 6H4 detected PrPc on Western blots of PNH platelets, demonstrating that the lack of 6H4 binding was not caused by PrPc truncation. Our results indicate that in the absence of GPI anchor, PrPc can be expressed intracellularly and up-regulated on the platelet membrane, likely in a transmembrane form with the C-terminal part of the molecule inserted into the cytoplasm.
Insights
Cellular prion protein (PrPc) is expressed differently in paroxysmal nocturnal hemoglobinuria (PNH) platelets lacking GPI anchors. Upon activation, PrPc appears on the platelet surface, suggesting a transmembrane form.
Area of Science:
- Biochemistry
- Hematology
- Cell Biology
Background:
- Cellular prion protein (PrPc) is a GPI-anchored glycoprotein.
- Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the absence of GPI-anchored proteins on hematopoietic cells.
- PrPc has a putative membrane-spanning section.
Purpose of the Study:
- To investigate the expression of PrPc on platelets from PNH patients.
- To determine the localization and form of PrPc in the absence of a GPI anchor.
Main Methods:
- Studied platelet PrPc expression in 8 PNH patients.
- Utilized monoclonal antibodies (mAbs) for PrPc detection.
- Performed Western blot analysis on PNH platelets.
Main Results:
- Resting PNH platelets (CD55(-)) lacked surface PrPc.
- Platelet activation led to surface expression of PrPc.
- PrPc was detected by N-terminal mAbs but not by C-terminal mAb 6H4 on the surface.
- Western blot confirmed PrPc integrity, ruling out truncation.
Conclusions:
- In the absence of a GPI anchor, PrPc can be expressed intracellularly.
- Platelet activation up-regulates PrPc on the cell membrane in PNH.
- PrPc likely adopts a transmembrane form with its C-terminus in the cytoplasm.
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