Ablation of Death-Associated Protein Kinase 1 Changes the Transcriptomic Profile and Alters Neural-Related Pathways
Ruomeng Li1, Shuai Zhi2,3, Guihua Lan1
1Fujian Key Laboratory of Translational Research in Cancer and Neurodegenerative Diseases, Institute of Basic Medicine, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China.
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.
Insights
Death-associated protein kinase 1 (DAPK1) regulates brain gene expression, impacting neurological diseases like Alzheimer's and epilepsy. Its absence alters gene profiles linked to neurodegeneration and synaptic pathways.
Area of Science:
- Neuroscience
- Molecular Biology
- Genetics
Background:
- Death-associated protein kinase 1 (DAPK1) is a kinase involved in neuronal functions and cell death.
- DAPK1 is upregulated in neurological conditions such as Alzheimer's disease (AD) and epilepsy.
- The role of DAPK1 in regulating brain gene expression and its link to neurological disorders remain unclear.
Purpose of the Study:
- To investigate the function and pathogenic role of DAPK1 in neurological diseases within the brain.
- To identify the gene expression profile regulated by DAPK1 in the brain.
- To explore potential therapeutic strategies targeting DAPK1.
Main Methods:
- Differential transcriptional profiling using RNA sequencing in DAPK1 knockout (DAPK1-KO) mice versus wild-type (WT) mice.
- Analysis of gene expression changes in various brain regions (cerebral cortex, hippocampus, brain stem, cerebellum) of both male and female mice.
- Bioinformatic analysis to identify affected neural-related pathways.
Main Results:
- Significant alterations in gene expression were observed in DAPK1-KO mice compared to WT mice across multiple brain regions.
- Affected genes are involved in key neural pathways, including Alzheimer's disease, Parkinson's disease, Huntington's disease, neurodegeneration, glutamatergic synapse, and GABAergic synapse.
- Potentially identified potassium voltage-gated channel subfamily A member 1 (Kcna1) as a modulator of DAPK1 in epilepsy.
Conclusions:
- DAPK1 plays a significant role in regulating gene expression networks within the brain.
- The identified gene profile provides insights into the pathological mechanisms of DAPK1 in neurological diseases.
- Findings suggest DAPK1 as a potential therapeutic target for neurological disorders.
