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.

Background: Allergic diseases (ADs) such as asthma are presumed risk factors for COVID-19 infection. However, recent observational studies suggest that the assumed correlation remains controversial. We therefore systematically investigated the genetic causal correlations of various ADs with COVID-19 infection/severity. Methods: We systematically performed a two-sample, bidirectional Mendelian randomization (MR) study of five ADs and the latest round of COVID-19 GWAS meta-analysis datasets (critically ill, hospitalized, and infection cases). We also validated the significant causal correlations and further elucidated underlying molecular mechanisms. Results: The most suitable MR method, for the first time, revealed significant causal effects of COVID-19 infection/severity on an increased asthma prevalence (OR>4.21), which obtained further validations. In contrast, asthma consistently demonstrated causally protective effects on critically ill and hospitalized COVID-19 cases upon adopting multiple MR methods (OR, 0.96–0.99). Our MR analyses also observed potential causal correlations of COVID-19 severity with atopic dermatitis, shrimp and peach allergy. Regarding underlying molecular mechanisms, we observed that COVID-19 phenotypes, especially those critically ill cases, were causally correlated to hematological traits and count data of immune-related cells. In contrast, ADs such as asthma and shrimp allergy may be causally correlated with COVID-19 infection/severity by affecting ACE2 protein expression. Conclusions: Our MR analyses suggest a bidirectional causal effect between COVID-19 phenotypes and ADs, especially asthma. The potential underlying molecular mechanisms of the causal effects may be beneficial in developing effective therapeutic strategies for allergy patients with COVID-19 infection and call for more attention to their physical characteristics upon showing long-term COVID-19 symptoms.

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