Pathogenic prions deviate PrP(C) signaling in neuronal cells and impair A-beta clearance.

Abstract

The subversion of the normal function exerted by the cellular prion protein (PrP(C)) in neurons by pathogenic prions is assumed to have a central role in the pathogenesis of transmissible spongiform encephalopathies. Using two murine models of prion infection, the 1C11 neuronal cell line and neurospheres, we document that prion infection is associated with the constitutive activation of signaling targets normally coupled with PrP(C), including the Fyn kinase, the mitogen-associated protein kinases ERK1/2 and the CREB transcription factor. PrP(C)-dependent signaling overactivation in infected cells is associated with the recruitment of p38 and JNK stress-associated kinases. Downstream from CREB, prion-infected cells exhibit reduced activity of the matrix metalloprotease (MMP)-9. As MMP-9 catalyzes the degradation of the amyloid A-beta peptide, the decrease in MMP-9 activity in prion-infected cells causes a significant impairment of the clearance of A-beta, leading to its accumulation. By exploiting two 1C11-infected clones accumulating high or moderate levels of prions, we show that the prion-induced changes are correlated with the level of infectivity. Of note, a dose-dependent increase in A-beta levels was also found in the cerebrospinal fluid of mice inoculated with these infected clones. By demonstrating that pathogenic prions trigger increases in A-beta levels through the deviation of PrP(C) signaling, our data argue that A-beta may exacerbate prion-induced toxicity.

• Authors: E Pradines, J Hernandez-Rapp, A Villa-Diaz, C Dakowski, H Ardila-Osorio, S Haik, B Schneider, J-M Launay, O Kellermann, J-M Torres, S Mouillet-Richard
• Journal: Cell death & disease (Cell Death Dis) Vol. 4 Pg. e456 (Jan 10 2013) ISSN: 2041-4889 [Electronic] England
• PMID: 23303130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amyloid beta-Peptides
• Cyclic AMP Response Element-Binding Protein
• Early Growth Response Protein 1
• PrPC Proteins
• Prions
• RNA, Small Interfering
• Proto-Oncogene Proteins c-fyn
• JNK Mitogen-Activated Protein Kinases
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• p38 Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 9

Topics

• Amyloid beta-Peptides (cerebrospinal fluid, metabolism)
• Animals
• Cell Line
• Cyclic AMP Response Element-Binding Protein (metabolism)
• Early Growth Response Protein 1 (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Neurons (cytology, metabolism)
• Phosphorylation
• PrPC Proteins (metabolism)
• Prion Diseases (metabolism, pathology)
• Prions (metabolism)
• Proto-Oncogene Proteins c-fyn (antagonists & inhibitors, genetics, metabolism)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Signal Transduction
• p38 Mitogen-Activated Protein Kinases (metabolism)