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Open Access Research

Activation of Pro-survival CaMK4β/CREB and Pro-death MST1 signaling at early and late times during a mouse model of prion disease

Rory H Shott1, Anna Majer34, Kathy L Frost3, Stephanie A Booth34 and Luis M Schang12*

Author Affiliations

1 Department of Biochemistry and Centre for Prions and Protein Folding Diseases (CPPFD), University of Alberta, Edmonton, AB, Canada

2 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, AB, Canada

3 Molecular PathoBiology, National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, MB, Canada

4 Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Winnipeg, MB, Canada

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Virology Journal 2014, 11:160  doi:10.1186/1743-422X-11-160

Published: 2 September 2014

Abstract

Background

The signaling pathways most critical to prion disease pathogenesis are as yet incompletely characterized. We have developed a kinomics approach to identify signaling pathways that are dysregulated during prion pathogenesis. The approach is sensitive and specific enough to detect signaling pathways dysregulated in a simple in vitro model of prion pathogenesis. Here, we used this approach to identify signaling pathways dysregulated during prion pathogenesis in vivo.

Methods

Mice intraperitoneally infected with scrapie (strain RML) were euthanized at 70, 90, 110, 130 days post-infection (dpi) or at terminal stages of disease (155–190 dpi). The levels of 139 protein kinases in brainstem-cerebellum homogenates were analyzed by multiplex Western blots, followed by hierarchical clustering and analyses of activation states.

Results

Hierarchical and functional clustering identified CaMK4β and MST1 signaling pathways as potentially dysregulated. Targeted analyses revealed that CaMK4β and its downstream substrate CREB, which promotes neuronal survival, were activated at 70 and 90 dpi in cortical, subcortical and brainstem-cerebellum homogenates from scrapie-infected mice. The activation levels of CaMK4β/CREB signaling returned to those in mock-infected mice at 110 dpi, whereas MST1, which promotes neuronal death, became activated at 130 dpi.

Conclusion

Pro-survival CaMK4β/CREB signaling is activated in mouse scrapie at earlier times and later inhibited, whereas pro-death MST1 signaling is activated at these later times.

Keywords:
Prion disease; Kinomics; Protein kinase; Multiplex Western blots; CaMK4β; CREB; MST1