Death-Associated Protein Kinase 1 (DAPK1) Signalling at the Crossroads of Apoptosis, Autophagy, and Post-transcriptional Cascades in Neurodegenerative Diseases

Abstract

Death-associated Protein Kinase-1 is a Ca2+/calmodulin- dependent serine/threonine protein kinase which controls various cellular processes and functions, including apoptosis, autophagy, and post-transcriptional processes, through multiple microRNAs. Increasing evidence suggests that, aberrant increase in the level of DAPK1 may result in neuronal injury and neurodegeneration by integration of multiple pathological processes such as excitotoxicity, neuroinflammation, and protein aggregation. DAPK1 contributes to disease progression through mechanisms such as NMDA receptor-mediated excitotoxicity, tau and α-synuclein hyperphosphorylation, apoptotic signaling, autophagic dysregulation, and synaptic loss. This review overviews the structural organization, regulatory mechanisms and role of DAPK1 in various cellular processes involved in neurodegeneration. This review discusses the complex transcriptional, post-transcriptional, and post-translational mechanisms governing DAPK1 activity, including regulation by transcription factors, microRNAs, phosphorylation events, and protein degradation pathways. Particular highlighting is given to the involvement of DAPK1 in both chronic and acute neurodegenerative disorders, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, diabetic encephalopathy, traumatic brain injury, and cerebral ischemic stroke. Finally, current therapeutic approaches based on the modulation of DAPK1 activity, including kinase inhibitors, competitive peptides, and gene-regulatory approaches, are reviewed, along with the challenges associated with target selectivity, blood–brain barrier penetration, and clinical translation. Collectively, this review emphasizes the therapeutic potential and discusses future directions for the development of disease-modifying interventions targeting DAPK1 in neurodegenerative diseases. Graphical abstract illustrating the central role of DAPK1 in neurodegenerative diseases. DAPK1 integrates apoptotic, autophagic, and post-transcriptional pathways, promoting tau pathology, α-synuclein aggregation, and excitotoxic neuronal death.