The Role And Mechanism Of CDH1-Mediated CDK5 Degradation In Ischemic Stroke

Stroke is the third-leading fatal disease in the world.Ischemic stroke caused by ischemia-reperfusion accounts for more than 80%of all types of strokes.Stroke possesses extremely high mortality and disability.Post-stroke cognitive dysfunction(PSCD)is recognized in 30%of the stroke patients,resulting in a high risk for developing dementia.Neural damages including excitotoxicity,oxidative stress,inflammatory response,and apoptosis induced by ischemia-reperfusion are the key factors in the prognosis of stroke.However,its specific mechanisms inducing these damages still remain unclear.No proper treatments have been found for stroke but clinical thrombolysis and mechanical thrombectomy.It is therefore urgent to unravel the mechanism of cerebral cell death caused by ischemic stroke,thus providing new treatment strategies for the prognostic intervention of stroke patients.Cyclin Dependent Kinase 5(CDK5)plays a pivotal role in maintaining the functions and survival of neuron,and in neuron death caused by stroke.We found that CDH1,a co-activator of E3 ubiquitin ligases APC/C,significantly increased in the brain of ischemia-reperfusion mice,accompanied with the decrease of CDK5 and synaptic-related proteins.CDH1 was distributed in different cell types in the nervous system,with a significantly higher amount in astrocytes.CDH1 levels gradually decreased during the development process of the mice.The distribution and expression of CDH1 suggest its important role in central nervous system,CDH1 was abnormally increased in the brain with ischemic stroke,leading to the degradation of CDK5 through the E3-mediated ubiquitination pathway.Meanwhile,astrocytes in the cerebral infarction area increased abnormally(GFAP levels were increased),and the levels of synaptic protein were also significantly reduced.CDH1 was overexpressed in the mouse brain by AAV mediated methods,which could improve the long-term learning and memory and reduce the GFAP expression in the infarcted area.These results indicate that CDH1 may affect neuron survival after stroke via regulating CDK5 expression.CDH1 maintains the homeostasis of various proteins in the cell,and changes in CDH1 protein levels would affect the function of many downstream substrates.The improvement of learning and cognition resulting from CDH1 overexpression needs further detailed investigations.In summary,our study found that excessive increased CDH1 in the ischemic stroke model regulated the degradation of CDK5 through interaction with CDH1.CDH1 may serve as a neuroprotective factor to improve long-term learning and memory.This study lays the foundation for stroke intervention researches using cell cycle regulation as the focusing point.Along with physical and biological approaches,cell cycle related proteins such as CDH1 and CDK5 can be used as targets to discover or develop novel neuroprotective drugs to improve the prognosis of stroke.