Table 1 A summary of DAPK1 dysregulation in common neurological diseases

Brain ischemia

Middle cerebral artery occlusion followed by reperfusion (transient ischemia)

Immediate down-regulation of DAPK1 mRNA in the ischemic core and up-regulation in the medial striatum; increased cleavage of DAPK1; reduction of pS308-DAPK1

Associated with ischemic neuronal cell death and brain infarction

[74]

Increased DAPK1 protein level and enzymatic activity; Interaction with ERK

Promotes the ischemic reperfusion-induced neuronal apoptosis

[99]

Binding to tau proteins in cortical neurons following brain ischemia

Phosphorylates the Ser262 of tau and causes dendritic spine injuries

[100]

Association with the NMDAR subunit GluN2B at post-synaptic sites

Phosphorylates the Ser1303 of GluN2B and promotes intraneuronal Ca²⁺ overload and cell death

[73]

Oxygen/glucose deprivation

Significant reduction of pS308-DAPK1; proteolytic cleavage of full-length DAPK1

Associates with ischemic neuronal cell death and brain infarction

[74]

Interaction with p53 in primary neurons

Phosphorylates the Ser23 of p53 and triggers both cell apoptosis and necrosis

[101]

Neonatal cerebral hypoxic ischemia by unilateral carotid ligation

DAPK1 catalytic activity elevated in the ischemic hippocampus in the late phase of hypoxic ischemia

May play a role in neuronal repair and differentiation in the recovery phase

[102]

Two-vessel occlusion model (global ischemia)

Up-regulation of DAPK1 mRNA in the cortex and hippocampus

Associated with ischemic neuronal cell death and brain infarction

[74]

Traumatic brain injury (TBI)

Diffuse axonal injury by lateral head rotation

Increased expression in hippocampal CA1 region and brainstem 1-day post injury, peaking at 3-day

Induces neuronal cell apoptosis and axonal degeneration

[103]

Closed-head TBI by weight drop

Significant elevation of protein level at 48 h post-TBI in the cerebral cortex

Promotes abnormal tau phosphorylation and accumulation, thus leading to axonal injuries and cognitive impairments

[104]

Controlled cortical impact of TBI

Elevated protein level at 1 week post TBI in the perilesional region of the cortex

Induces neuronal apoptosis and GluN2B phosphorylation

[105]

Epilepsy

Brief seizures induced by intra-amygdala kainic acid (KA) injection

Association with p53 and undergoes proteolytic cleavage in ipsilateral hippocampus

Mediates seizure-induced neuronal death in the hippocampus

[106]

Pentylenetetrazol (PTZ) exposure-induced seizure

Robust increase in DAPK1 activity but not protein level in the cortex and hippocampus after acute PTZ treatment; remarkable upregulation of DAPK1 protein level in the cortex and hippocampus following chronic low-dose PTZ kindling

Stimulates the phosphorylation of GluN2B and induces seizure phenotypes

[76]

Seizures induced by intraperitoneal injection of KA

Significant activation of DAPK1 revealed by an upregulation of ERK-induced pS735-DAPK1 in cortex and hippocampus after KA treatment

Triggers neuronal apoptosis and potentiates seizure activity

[77]

Parkinson’s disease (PD)

MPTP-induced mouse PD model

Remarkable increase of DAPK1 protein level in striatal neurons of MPTP-treated mice, while the mRNA expression is unchanged

Induces dopaminergic neuron death, promotes synucleinopathy and exacerbates motor deficits in mice

[82, 107, 108]

Depression

Chronic unpredictable stress (CUS)-induced rat depression model

Upregulation of both the protein level and the catalytic activity of DAPK1 in the medial prefrontal cortex of CUS rats; enhancement of DAPK1-GluN2B association

Disrupts the NMDAR signaling and induces synaptic dysfunction as well as depressive-like behavior

[109]

CUS-induced mouse depression model

Significant increases in the protein level and activity of DAPK1 in the hippocampus of mice exposed to CUS

Facilitates abnormal tau phosphorylation and accumulation, and results in depressive-like behavior

[110]

Alzheimer’s disease (AD)

Brain tissues of AD patients

Marked increase in the protein level of DAPK1 in the hippocampus of AD patients compared with age-matched controls, while the mRNA expression levels are comparable

Associates with aberrant tau- and APP phosphorylation, and contributes to both tau and Aβ pathologies

[78, 79]

Plasma samples of AD patients

Higher plasma DAPK1 protein level in AD than in control individuals

Negatively correlated with the cognitive ability

[111]

Tg2576-APPswe mouse model

Age-dependent activation of DAPK1 in the excitatory pyramidal neurons in the entorhinal cortex of Tg2576 mice while the total DAPK1 protein level remains constant

Mediates synaptic degeneration in the excitatory pyramidal neurons of the entorhinal cortex

[112]

Human tau (hTau) transgenic mouse model

Elevated DAPK1 protein level expression in cortex and hippocampus of 10-month hTau mice

Shows correlation with tau phosphorylation at Ser262

[113]

PS1 V97L transgenic mouse model

Increased DAPK1 protein level in the hippocampus of 6-month and 9-month mice

Increases the Ser1303 phosphorylation of GluN2B

[111]

Huntington’s disease (HD)

YAC128 HD mouse model

Increased DAPK1 protein level and activation in the cortex and striatum of 1-month mouse HD model, while the DAPK1 mRNA level remains constant

Facilitates GluN2B phosphorylation at Ser1303 and damages synaptic functions

[114]