Activation of Pro-survival CaMK4ß/CREB and Pro-death MST1 signaling at early and late times during a mouse model of prion disease

Shott, Rory H; Majer, Anna; Frost, Kathy L; Booth, Stephanie A; Schang, Luis M

Activation of Pro-survival CaMK4ß/CREB and Pro-death MST1 signaling at early and late times during a mouse model of prion disease

dc.contributor.author	Shott, Rory H
dc.contributor.author	Majer, Anna
dc.contributor.author	Frost, Kathy L
dc.contributor.author	Booth, Stephanie A
dc.contributor.author	Schang, Luis M
dc.date.accessioned	2014-09-15T23:06:02Z
dc.date.available	2014-09-15T23:06:02Z
dc.date.issued	2014-09-02
dc.date.updated	2014-09-15T23:06:02Z
dc.description.abstract	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.
dc.description.version	Peer Reviewed
dc.identifier.citation	Virology Journal. 2014 Sep 02;11(1):160
dc.identifier.doi	http://dx.doi.org/10.1186/1743-422X-11-160
dc.identifier.uri	http://hdl.handle.net/1993/24044
dc.language.rfc3066	en
dc.rights	open access	en_US
dc.rights.holder	Rory H Shott et al.; licensee BioMed Central Ltd.
dc.title	Activation of Pro-survival CaMK4ß/CREB and Pro-death MST1 signaling at early and late times during a mouse model of prion disease
dc.type	Journal Article