Abstract
The subversion of the normal function exerted by the cellular prion protein (PrPC) 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 PrPC, including the Fyn kinase, the mitogen-associated protein kinases ERK1/2 and the CREB transcription factor. PrPC-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 PrPC signaling, our data argue that A-beta may exacerbate prion-induced toxicity.
Highlights
Depletion of neuronal cellular prion protein (PrPC) in scrapie-infected mice impedes transmissible spongiform encephalopathy (TSE) pathogenesis despite massive extraneuronal disease-associated scrapie prion protein (PrPSc) accumulation.[2]
We further show that the cascade of PrPSc-mediated events culminates with a decreased clearance of A-beta in 1C11Fkinfected cells, and that A-beta levels are increased in the cerebrospinal fluid (CSF) of prion-infected mice
A growing body of evidence argues that PrPSc exerts its neurotoxic action through the corruption of PrPC normal function.[4,7]
Summary
Depletion of neuronal PrPC in scrapie-infected mice impedes TSE pathogenesis despite massive extraneuronal PrPSc accumulation.[2]. PrPSc neurotoxicity may rather involve some toxic gain of PrPC function This notion is supported by the development of a spontaneous neurodegenerative illness in transgenic mice overexpressing wild-type PrPC by 5- to 10-fold.[6] Unraveling the physiological function of PrPC in neuronal cells represents a major issue to decipher the cellular and molecular events leading to neurodegeneration in TSEs.[7] Answers to this question may have a broad significance in the field of neurodegenerative disorders because PrPC appears to mediate the toxicity of diverse beta-sheet rich oligomers, including the beta-amyloid peptide A-beta.[8]. The identification of various targets within PrPC-mediated cascades provides molecular readouts to probe PrPSc action
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