Activation of Pro-survival CaMK4 beta/CREB and Pro-death MST1 signaling at early and late times during a mouse model of prion disease

作者：Shott Rory H; Majer Anna; Frost Kathy L; Booth Stephanie A; Schang Luis M^*

来源：Virology Journal, 2014, 11(1): 160.

DOI：10.1186/1743-422X-11-160

• Prion disease
• Kinomics
• Protein kinase
• Multiplex Western blots
• CaMK4 beta
• CREB
• MST1

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. %26lt;br%26gt;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. %26lt;br%26gt;Results: Hierarchical and functional clustering identified CaMK4 beta and MST1 signaling pathways as potentially dysregulated. Targeted analyses revealed that CaMK4 beta 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 CaMK4 beta/CREB signaling returned to those in mock-infected mice at 110 dpi, whereas MST1, which promotes neuronal death, became activated at 130 dpi. %26lt;br%26gt;Conclusion: Pro-survival CaMK4 beta/CREB signaling is activated in mouse scrapie at earlier times and later inhibited, whereas pro-death MST1 signaling is activated at these later times.

• 出版日期2014-9-2