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Investigating the Spreading and Toxicity of Prion-like Proteins Using the Metazoan Model Organism C. elegans
Published on: January 8, 2015
Lymphoid signal transduction mechanisms linked to cellular prion protein
I E Mazzoni1, H C Ledebur, E Paramithiotis
1Caprion Pharmaceuticals, Montreal, QC H4S 2C8, Canada.
Insights
The prion protein (PrPC) plays a role in immune function. Mice lacking PrPC show reduced splenocyte proliferation and altered protein signaling pathways, indicating its importance in immune responses.
Area of Science:
- Immunology
- Cell Biology
- Neuroscience
Background:
- The cellular prion protein (PrPC) is a cell surface protein found in various cells, including lymphoid cells.
- Its precise function, particularly in immune responses, remains incompletely understood.
Purpose of the Study:
- To investigate the role of PrPC in immune cell activation and signaling.
- To compare lectin-induced mitogenesis and cell signaling pathways in splenocytes from wild-type and PrPC-deficient mice.
Main Methods:
- Splenocytes from wild-type and Prnp0/0 mice were stimulated with lectins (Concanavalin A and phytohemagglutinin).
- Proliferation was assessed by 3H-thymidine incorporation.
- Protein phosphorylation patterns (PKC, MAPK) and calcium fluxes were analyzed.
Main Results:
- Prnp0/0 splenocytes exhibited significantly reduced proliferation, especially early in activation.
- Defects in the phosphorylation of Protein Kinase C (PKC) alpha/beta and p44/42 MAPK were observed in Concanavalin A-activated Prnp0/0 splenocytes.
- Calcium fluxes were comparable between wild-type and Prnp0/0 splenocytes, suggesting they are not directly involved in the observed signaling defects.
Conclusions:
- The absence of PrPC impairs splenocyte activation and proliferation.
- PrPC appears to modulate PKCalpha/beta phosphorylation, impacting its role in regulating splenocyte mitosis.
- These findings support a role for PrPC in modulating immune function.
Abstract:
The normal cellular isoform of the prion protein (PrPC) is a glycosylphosphatidylinositol-anchored cell surface protein that is expressed widely, including in lymphoid cells. We compared lectin-induced mitogenesis and selected cell signaling pathways in splenocytes from wild-type BALB/c mice and Zrch Prnp0/0 (PrP0/0) mice bred on a BALB/c background for more than 10 generations. 3H-thymidine incorporation induced by concanavalin A (Con A) or phytohemagglutinin (PHA) was significantly reduced in PrP0/0 splenocytes, most prominently early in activation (24 and 48 h). Con A activation in PrP0/0 splenocytes was associated with differences in the phosphorylation (P) patterns of protein kinase C (PKC alpha/beta, but not delta) and the PKC downstream effectors p44/42MAPK (mitogen-activated protein kinase). P-PKC and P-MAPK profiles were similar in wild-type and PrP0/0 splenocytes following PMA treatment, indicating that the ability of these 2 enzymes to be phosphorylated is not impaired in the absence of PrPC. Con A-induced calcium fluxes, monitored by indo-1 fluorescence, were equivalent in PrP0/0 and PrP+/+ splenocytes, suggesting that calcium-dependent mechanisms are not directly implicated in the differential phosphorylation patterns or mitotic responses. Our data indicate that PrP0/0 splenocytes display defects in upstream or downstream mechanism(s) that modulate PKCalpha/beta phosphorylation, which in turn affects its capacity to regulate splenocyte mitosis, consistent with a role for PrPC in immune function.
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