Zipper-interacting Protein Kinase Modulates Gene Expression Linked to Synaptic and Neuronal Processes after Traumatic...

Traumatic brain injury (TBI) is one of the leading causes of disability and death worldwide. Zipper-interacting protein kinase (ZIPK) is a serine/threonine kinase, whose main function is to regulate cell death, inflammation and smooth muscle contraction. ZIPK dysregulation has been implicated in a range of neurological disorders, including ischemic stroke, Alzheimer's disease, and TBI. Downregulation of ZIPK expression level or pharmacological inhibition of ZIPK kinase activity alleviates neuronal injury. ZIPK has a nuclear localization signal sequence and transcriptional regulatory activity. However, whether ZIPK affects gene expression in the brain after TBI remains unknown. In this study, transcriptome sequencing analysis was employed to compare the differences in gene expression in the peri-injury tissues between wild-type and ZIPK heterozygous mice after TBI. Our results indicated that ZIPK regulates a variety of genes and signaling pathways, including pathways related to synaptic function, learning and memory, vascular function, and DNA replication, after TBI. Gene set enrichment analysis highlighted the important role of ZIPK in synapses during TBI. In addition, quantitative real-time PCR analysis validated changes in the expression of multiple genes related to synaptic function, including Drd1, Grin2a, Grin2b, Dlg4, Fn1, and Pecam1, which were identified by gene correlation analysis and protein-protein interaction analysis. Immunofluorescence staining revealed that partial deletion of ZIPK alleviates synaptic protein loss induced by TBI. In conclusion, our data suggest a role for ZIPK in the regulatory network in the brain, especially in relation to synaptic damage, after TBI, providing a new therapeutic strategy for this condition.