Recent evidence suggests that abnormal activation of cyclin-dependent kinase 5 
(cdk5) is a critical prodeath signal in stroke. However, the mechanism(s) by 
which cdk5 promotes death is unclear. Complicating the role of cdk5 are the 
observations that cdk5 can exist in multiple cellular regions and possess both 
prosurvival and prodeath characteristics. In particular, the critical role of 
cytoplasmic or nuclear cdk5 in neuronal jury, in vivo, is unclear. Therefore, we 
determined where cdk5 was activated in models of ischemia and how manipulation 
of cdk5 in differing compartments may affect neuronal death. Here, we show a 
critical function for cytoplasmic cdk5 in both focal and global models of 
stroke, in vivo. Cdk5 is activated in the cytoplasm and expression of DNcdk5 
localized to the cytoplasm is protective. Importantly, we also demonstrate the 
antioxidant enzyme Prx2 (peroxiredoxin 2) as a critical cytoplasmic target of 
cdk5. In contrast, the role of cdk5 in the nucleus is context-dependent. 
Following focal ischemia, nuclear cdk5 is activated and functionally relevant 
while there is no evidence for such activation following global ischemia. 
Importantly, myocyte enhancer factor 2D (MEF2D), a previously described nuclear 
target of cdk5 in vitro, is also phosphorylated by cdk5 following focal 
ischemia. In addition, MEF2D expression in this paradigm ameliorates death. 
Together, our results address the critical issue of cdk5 activity 
compartmentalization, as well as define critical substrates for both cytoplasmic 
and nuclear cdk5 activity in adult models of stroke.