Pathogenic prions deviate PrPC 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.
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E Pradines, J Hernandez-Rapp, A Villa-Diaz, C Dakowski, H Ardila-Osorio, et al.. Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance. Cell Death and Disease , Nature Publishing Group, 2013, 4, pp.e456. ⟨10.1038/cddis.2012.195⟩. ⟨hal-01548467⟩

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