Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways in the Brain

Abstract

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin-dependent serine/threonine kinase, mediates various neuronal functions, including cell death. Abnormal upregulation of DAPK1 is observed in human patients with neurological diseases, such as Alzheimer’s disease (AD) and epilepsy. Ablation of DAPK1 expression and suppression of DAPK1 activity attenuates neuropathology and behavior impairments. However, whether DAPK1 regulates gene expression in the brain, and whether its gene profile is implicated in neuronal disorders, remains elusive. To reveal the function and pathogenic role of DAPK1 in neurological diseases in the brain, differential transcriptional profiling was performed in the brains of DAPK1 knockout (DAPK1-KO) mice compared with those of wild-type (WT) mice by RNA sequencing. We showed significantly altered genes in the cerebral cortex, hippocampus, brain stem, and cerebellum of both male and female DAPK1-KO mice compared to those in WT mice, respectively. The genes are implicated in multiple neural-related pathways, including: AD, Parkinson’s disease (PD), Huntington’s disease (HD), neurodegeneration, glutamatergic synapse, and GABAergic synapse pathways. Moreover, our findings imply that the potassium voltage-gated channel subfamily A member 1 (Kcna1) may be involved in the modulation of DAPK1 in epilepsy. Our study provides insight into the pathological role of DAPK1 in the regulatory networks in the brain and new therapeutic strategies for the treatment of neurological diseases.

Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease

“…Functional studies demonstrated that DAPK1 KO mice have different presynaptic components in hippocampus compared with the WT mice, as evidenced by the increased paired-pulse ratio and reduced glutamate release probability in the hippocampus of KO mice [ 164 ]. Our transcriptomic analysis in DAPK1 KO and WT mice suggested that DAPK1 ablation globally changes the transcriptional profile in multiple brain regions and significantly regulates genes related to glutamatergic and GABAergic synaptic pathways [ 185 ]. The potential involvement of DAPK1 in modulating synaptic transmission and plasticity hints that DAPK1 dysregulation in AD may additionally cause synaptic impairments.…”