Role of Erk1/2 activation in prion disease pathogenesis: Absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression

LaCasse, Rachel; Striebel, James F.; Favara, Cynthia; Kercher, Lisa; Chesebro, Bruce

doi:10.1016/j.jneuroim.2008.02.009

Cited by 22 publications

(17 citation statements)

References 43 publications

(53 reference statements)

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“…We show that, in both 1C11 5-HT neuronal cells and differentiated wild-type neurospheres, prion infection is associated with the constitutive activation of several PrP C proximal targets, including the Fyn kinase, ERK1/2 MAP kinases, the CREB transcription factor and its target gene Egr-1. Our data have to be brought together with in vivo observations, showing increased activities of Src kinases, 23 MAP kinases 24, 25 and CREB 25 in the brains of scrapie-infected mice.…”

Section: Discussionmentioning

confidence: 57%

Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance

Pradines

Hernandez-Rapp

Villa-Diaz³

et al. 2013

Cell Death Dis

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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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Section: Discussionmentioning

confidence: 57%

Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance

Pradines

Hernandez-Rapp

Villa-Diaz³

et al. 2013

Cell Death Dis

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“…For example, mice lacking expression of cytokine receptor IL-1 receptor type I (54) or chemokine receptor CXCR3 (48) showed increased survival following scrapie agent infection, indicating that signaling via these receptors might contribute to disease pathogenesis. In contrast, other studies using mice lacking expression of CCR1 (31) or having a mutation affecting TLR4 (Toll-like receptor 4) signaling (55) showed decreased survival after scrapie, indicating that signaling via these receptors might contribute to damage control during prion infection. Last, mice with deficient expression of cytokine TNF or IL-6 had no alteration in survival after intracerebral scrapie agent infection (34).…”

Section: Discussionmentioning

confidence: 81%

Analysis of Protein Levels of 24 Cytokines in Scrapie Agent-Infected Brain and Glial Cell Cultures from Mice Differing in Prion Protein Expression Levels

Tribouillard-Tanvier

Striebel

Peterson

et al. 2009

J Virol

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Activation of microglia and astroglia is seen in many neurodegenerative diseases including prion diseases. Activated glial cells produce cytokines as a protective response against certain pathogens and as part of the host inflammatory response to brain damage. In addition, cytokines might also exacerbate tissue damage initiated by other processes. In the present work using multiplex assays to analyze protein levels of 24 cytokines in scrapie agent-infected C57BL/10 mouse brains, we observed elevation of CCL2, CCL5, CXCL1, CXCL10, granulocyte-macrophage colony-stimulating factor (GM-CSF), gamma interferon (IFN-␥), interleukin 1␣ (IL-1␣), IL-1␤, IL-6, and IL-12p40. Scrapie agent-infected wild-type mice and transgenic mice expressing anchorless prion protein (PrP) had similar cytokine responses in spite of extensive differences in neuropathology. Therefore, these responses may be primarily a reaction to brain damage induced by prion infection rather than specific inducers of a particular type of pathology. To study the roles of astroglia and microglia in these cytokine responses, primary glial cultures were exposed to scrapie agent-infected brain homogenates. Microglia produced only IL-12p40 and CXCL10, whereas astroglia produced these cytokines plus CCL2, CCL3, CCL5, CXCL1, G-CSF, IL-1␤, IL-6, IL-12p70, and IL-13. Glial cytokine responses from wild-type mice and transgenic mice expressing anchorless PrP differed only slightly, but glia from PrP-null mice produced only IL-12p40, indicating that PrP expression was required for scrapie agent induction of other cytokines detected. The difference in cytokine response between microglia and astroglia correlated with 20-fold-higher levels of PrP expression in astroglia versus microglia, suggesting that high-level PrP expression on astroglia might be important for induction of certain cytokines.

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“…Therefore, microglia appear to be on the one hand attempting to restore homeostasis introduced by misfolded proteins that act as seeds, but in regions of neurodegeneration, the microglia enter into a cycle of innate immune activation. Previous studies have demonstrated that, by altering specific aspects of the innate immune response by KO of specific pro- or anti-inflammatory genes, the severity of disease can be altered [45–51]. Furthermore, by inhibiting microglial proliferation during disease, and thus reducing the number of microglia exhibiting an activated innate immune response, other studies have shown a prolongation of incubation period in prion disease [52].…”

Section: Discussionmentioning

confidence: 99%

Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration

et al. 2016

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Protein misfolding is common across many neurodegenerative diseases, with misfolded proteins acting as seeds for "prion-like" conversion of normally folded protein to abnormal conformations. A central hypothesis is that misfolded protein accumulation, spread, and distribution are restricted to specific neuronal populations of the central nervous system and thus predict regions of neurodegeneration. We examined this hypothesis using a highly sensitive assay system for detection of misfolded protein seeds in a murine model of prion disease. Misfolded prion protein (PrP) seeds were observed widespread throughout the brain, accumulating in all brain regions examined irrespective of neurodegeneration. Importantly, neither time of exposure nor amount of misfolded protein seeds present determined regions of neurodegeneration. We further demonstrate two distinct microglia responses in prion-infected brains: a novel homeostatic response in all regions and an innate immune response restricted to sites of neurodegeneration. Therefore, accumulation of misfolded prion protein alone does not define targeting of neurodegeneration, which instead results only when misfolded prion protein accompanies a specific innate immune response.

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Role of Erk1/2 activation in prion disease pathogenesis: Absence of CCR1 leads to increased Erk1/2 activation and accelerated disease progression

Cited by 22 publications

References 43 publications

Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance

Pathogenic prions deviate PrPC signaling in neuronal cells and impair A-beta clearance

Analysis of Protein Levels of 24 Cytokines in Scrapie Agent-Infected Brain and Glial Cell Cultures from Mice Differing in Prion Protein Expression Levels

Distribution of Misfolded Prion Protein Seeding Activity Alone Does Not Predict Regions of Neurodegeneration

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