Death-Associated Protein Kinase 1 Phosphorylation in Neuronal Cell Death and Neurodegenerative Disease

Abstract

Regulated neuronal cell death plays an essential role in biological processes in normal physiology, including the development of the nervous system. However, the deregulation of neuronal apoptosis by various factors leads to neurodegenerative diseases such as ischemic stroke and Alzheimer’s disease (AD). Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase that activates death signaling and regulates apoptotic neuronal cell death. Although DAPK1 is tightly regulated under physiological conditions, DAPK1 deregulation in the brain contributes to the development of neurological disorders. In this review, we describe the molecular mechanisms of DAPK1 regulation in neurons under various stresses. We also discuss the role of DAPK1 signaling in the phosphorylation-dependent and phosphorylation-independent regulation of its downstream targets in neuronal cell death. Moreover, we focus on the major impact of DAPK1 deregulation on the progression of neurodegenerative diseases and the development of drugs targeting DAPK1 for the treatment of diseases. Therefore, this review summarizes the DAPK1 phosphorylation signaling pathways in various neurodegenerative diseases.

DAPK1 Promotes Extrasynaptic GluN2B Phosphorylation and Striatal Spine Instability in the YAC128 Mouse Model of Huntington Disease

“…S1303 phosphorylation has also been associated with enhanced GluN2B surface expression in neurons (Sanz-Clemente et al, 2013), suggesting that DAPK1 may act as a signal amplifier for exGluN2B under pathological conditions. Accordingly, numerous genetic and pharmacological DAPK1targeting approaches have demonstrated neuroprotective and synapto-protective benefits in animal models of stroke, excitotoxicity, Alzheimer's disease, Parkinson's disease, and chronic stress (Li et al, 2018;Kim et al, 2019;Su et al, 2019).…”

Peptidyl-Prolyl Cis/Trans Isomerase Pin1 and Alzheimer’s Disease

“…Recently, death-associated protein kinase 1 (DAPK1) has been found to play essential roles in neuronal cell death and various neurodegenerative diseases, including AD (Chen et al, 2019;Kim et al, 2019). Importantly, DAPK1 is capable of phosphorylating Pin1 at S71 in the PPIase domain, thus inhibiting its nuclear localization, prolyl isomerase activity, and cellular function (Lee et al, 2011a,b).…”

“…In addition, therapeutic strategies targeting Pin1 also focus on the upstream regulators of Pin1 such as DAPK1 or targets such as cis or trans pT231-tau. Indeed, the inhibition of DAPK1 has been shown to attenuate tau hyperphosphorylation and Aβ production (Kim et al, 2014(Kim et al, , 2016(Kim et al, , 2019You et al, 2017;Chen et al, 2019). Thus, Pin1-related therapeutic strategies might be valuable in the treatment of AD.…”

Post-translational Modifications of the Peptidyl-Prolyl Isomerase Pin1

“…Death-associated protein kinase 1 (DAPK1) directly binds to and phosphorylates Pin1 on Ser71, which is located in the substrate binding loop consisting of residues 63-80 in the PPIase domain (Bialik and Kimchi, 2011;Lee et al, 2011a,b). DAPK1 is a calcium/calmodulin-dependent Ser/Thr kinase that is involved in cell death, and its deregulation is implicated in cancer and AD (Cohen et al, 1997;Inbal et al, 1997;Kissil et al, 1997;Kim et al, 2014Kim et al, , 2016Kim et al, , 2019Zhao et al, 2015;You et al, 2017;Chen et al, 2019). Pin1 phosphorylation on Ser71 by DAPK1 inhibits the catalytic activity of Pin1, specifically suppressing the ability of Pin1 to activate transcription factors and stabilize proteins, blocks Pin1 nuclear localization, and attenuates the centrosome amplification, chromosome instability and cell transformation induced by Pin1 (Lee et al, 2011a).…”