Essential role of cytoplasmic cdk5 and Prx2 in multiple ischemic injury models, in vivo.
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.
Rashidian
Juliet
J
Neuroscience Group, Ottawa Health Research Institute, Ottawa, Ontario K1H 8M5, Canada.
Rousseaux
Maxime W
MW
Venderova
Katerina
K
Qu
Dianbo
D
Callaghan
Steve M
SM
Phillips
Maryam
M
Bland
Ross J
RJ
During
Matthew J
MJ
Mao
Zixu
Z
Slack
Ruth S
RS
Park
David S
DS
D000818:Animals; D002545:Brain Ischemia / Q000209:etiology / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002531:Cerebellum / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism*; D004195:Disease Models, Animal; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000378:metabolism; D054464:Peroxiredoxins / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000150:complications
D054464:Peroxiredoxins; D051360:Cyclin-Dependent Kinase 5