Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

Duda, Przemysław; Wisniewski, J.; Wójtowicz, T.; Wójcicka, Olga; Jaśkiewicz, Michał; Drulis−Fajdasz, Dominika; Rakus, Dariusz; McCubrey, James A.; Gizak, Agnieszka

doi:10.1080/14728222.2018.1526925

Cited by 107 publications

(67 citation statements)

References 171 publications

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“…Among the known growth factors, insulin-like growth factor 1 [99], platelet-derived growth factor BB [100], hepatocyte growth factor [101], fibroblast growth factor 2 [102], epidermal growth factor, and transforming growth factor (TGF-)β [103] as well as stem cell factor [104] have been demonstrated to inhibit GSK3 activity. In turn, activation of Ser21/9-phosphorylated GSK3 can be mediated via protein phosphatases (PP) 1, 2A [79,105], and 2B [15].…”

Section: Posttranslational Modificationsmentioning

confidence: 99%

“…GSK3 acts a potent driver of inflammation, rendering GSK3 inhibitors a promising target of anti-inflammatory research [17,121]. It is well established that enzymatically active GSK3 acts as a crucial positive regulator of pro-inflammatory cytokines (e.g., TNF, interleukin (IL-)1β, IL-6 [15], IL-17, IL-18 [122], IL-23 [94], IL-12, IFN-γ [17]), chemokines (IL-8 [122], C-C motif chemokine ligand (CCL) 2 [17], 3, 4 [123], and 12, C-X-C motif chemokine ligand (CXCL) 1, 2, 5 [17], and 10 [124]), and further pro-inflammatory mediators (e.g., nitric oxide (NO) [125] or prostaglandin E2 [126]). Vice versa, anti-inflammatory cytokines, such as IL-2 [127], IL-10 [90], IL-22 [128], IL-33 [129], and IL-1 receptor antagonist [130], are negatively regulated by GSK3.…”

Section: Cytokine Expressionmentioning

confidence: 99%

“…GSK3 also plays a role in the pathogenesis of common diseases, e.g., neurological/neurodegenerative diseases [13,15]; diabetes mellitus [16]; inflammatory diseases [17], such as rheumatoid arthritis [18]; and different types of cancer [19]. Moreover, GSK3 is also of priming phosphorylation has to be mediated by another kinase, GSK3 is able to perform multiple successive phosphorylation steps at substrates containing a series of adjacent consensus sequences, thus generating its own priming phosphorylation for further phosphorylation events [38].…”

Section: Introductionmentioning

confidence: 99%

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GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

102

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GSK3 has been implicated for years in the regulation of inflammation and addressed in a plethora of scientific reports using a variety of experimental (disease) models and approaches. However, the specific role of GSK3 in the inflammatory process is still not fully understood and controversially discussed. Following a detailed overview of structure, function, and various regulatory levels, this review focusses on the immunoregulatory functions of GSK3, including the current knowledge obtained from animal models. Its impact on pro-inflammatory cytokine/chemokine profiles, bacterial/viral infections, and the modulation of associated pro-inflammatory transcriptional and signaling pathways is discussed. Moreover, GSK3 contributes to the resolution of inflammation on multiple levels, e.g., via the regulation of pro-resolving mediators, the clearance of apoptotic immune cells, and tissue repair processes. The influence of GSK3 on the development of different forms of stimulation tolerance is also addressed. Collectively, the role of GSK3 as a kinase balancing the initiation/perpetuation and the amelioration/resolution of inflammation is highlighted.

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Section: Posttranslational Modificationsmentioning

confidence: 99%

Section: Cytokine Expressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

Hoffmeister

Diekmann

Brand

et al. 2020

Cells

102

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“…Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Extracellular factors, such as insulin or insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor 1β (TGF-1β), acting via the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, inhibit GSK3β by phosphorylation of Ser9 of the kinase [14][15][16].…”

mentioning

confidence: 99%

“…The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Extracellular factors, such as insulin or insulin-like growth factor 1 (IGF-1), epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and transforming growth factor 1β (TGF-1β), acting via the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathway, inhibit GSK3β by phosphorylation of Ser9 of the kinase [14][15][16]. The same effect is mediated by mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway activity upon EGF, fibroblast growth factor (FGF), PDGF, nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF) stimulation, and as a result of cytokine action via p38 MAPK [17][18][19].…”

mentioning

confidence: 99%

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Duda

Hajka

Wójcicka

et al. 2020

Cells

Self Cite

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Glycogen synthase kinase 3β (GSK3β), originally described as a negative regulator of glycogen synthesis, is a molecular hub linking numerous signaling pathways in a cell. Specific GSK3β inhibitors have anti-depressant effects and reduce depressive-like behavior in animal models of depression. Therefore, GSK3β is suggested to be engaged in the pathogenesis of major depressive disorder, and to be a target and/or modifier of anti-depressants' action. In this review, we discuss abnormalities in the activity of GSK3β and its upstream regulators in different brain regions during depressive episodes. Additionally, putative role(s) of GSK3β in the pathogenesis of depression and the influence of anti-depressants on GSK3β activity are discussed.Cells 2020, 9, 727 2 of 26 any of the groups listed above. Additionally, electroconvulsive therapy, conducted for the first time in 1938, is still widely used in the treatment of MDD, especially in its drug-refractory form [5].Although the monoaminergic hypothesis has led to the invention of many successful therapeutic strategies based on the elevation of levels of NA and 5-HT in the synaptic cleft, it does not explain the anti-depressant effect of lithium and the rapid action of ketamine in the treatment of mood disorders [6]. Therefore, factors other than neurotransmission must be taken into consideration in the context of the MDD pathogenesis. One of them is glycogen synthase kinase 3β (GSK3β) signaling. Glycogen Synthase Kinase 3βGSK3 was isolated in 1980, from rabbit skeletal muscle, and described as a highly specific serine/threonine kinase for glycogen synthase [7]. There are two isozymes of GSK3, α and β, and both are expressed at similar levels in the mouse brain [8]. In the human brain, the β isozyme predominates [9]. Therefore, GSK3β is expected to be crucial for the human central nervous system functioning. The activity of GSK3β is regulated positively and negatively by phosphorylation on Tyr216 and Ser9, respectively [10,11]. Whereas phosphorylation of the residue Tyr216 occurs during the GSK3β translation process and results in a synthesis of the fully activated kinase, Ser9 phosphorylation seems to be the main regulatory modification during the enzyme lifespan [12]. Ser9-phosphorylated GSK3β remains inhibited, and dephosphorylation of the residue results in the disinhibition (activation) of the kinase.GSK3β is part of numerous cellular signaling pathways, and its activity can be regulated, directly or indirectly, by several kinases, phosphatases, and proteases. The wide spectrum of GSK3β substrates, including transcription factors, glycolytic enzymes, pro-and anti-apoptotic factors, mitochondrial channels, membrane receptors, and cytoskeleton-associated proteins, makes GSK3β a central point of the cell homeostasis maintenance [13]. The activity of GSK3β affects energy metabolism, cell survival, proliferation, apoptosis, membrane polarity, internalization of the synaptic receptors, neuroplasticity, neurotransmission, amyloid processing, and many other processes [13].Ex...

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Discovery of novel α‐carboline derivatives as glycogen synthase kinase‐3β inhibitors for the treatment of Alzheimer's disease

Chen

Liu

et al. 2022

Archiv der Pharmazie

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Alzheimer's disease (AD) is a chronic and progressive neurodegenerative disease, characterized by irreversible cognitive impairment, memory loss, and behavioral disturbances, ultimately resulting in death. The critical roles of glycogen synthase kinase-3β (GSK-3β) in tau pathology have also received considerable attention.Based on molecular docking studies, a series of novel α-carboline derivatives were designed, synthesized, and evaluated as GSK-3β inhibitors for their various biological activities. Among them, compound ZCH-9 showed the most potent inhibitory activity against GSK-3β, with an IC 50 value of 1.71 ± 0.09 µM. The cytotoxicity assay showed that ZCH-9 had low cytotoxicity toward the cell lines SH-SY5Y, HepG2, and HL-7702. Moreover, Western blot analysis indicated that ZCH-9 effectively inhibited hyperphosphorylation of the tau protein in okadaic acid-treated SH-SY5Y cells. The binding mode between ZCH-9 and GSK-3β was analyzed and further clarified throughout the molecular dynamics simulations. In general, these results suggested that the α-carboline-based small-molecule compounds could serve as potential candidates targeting GSK-3β for the treatment of AD.

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Targeting GSK3 signaling as a potential therapy of neurodegenerative diseases and aging

Cited by 107 publications

References 171 publications

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

GSK3: A Kinase Balancing Promotion and Resolution of Inflammation

GSK3β: A Master Player in Depressive Disorder Pathogenesis and Treatment Responsiveness

Discovery of novel α‐carboline derivatives as glycogen synthase kinase‐3β inhibitors for the treatment of Alzheimer's disease

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