The Potential Role of Glycogen Synthase Kinase 3 Inhibitors as Amyotrophic Lateral Sclerosis Pharmacological Therapy

2011 ◽  
Vol 18 (20) ◽  
pp. 3028-3034 ◽  
Author(s):  
V. Palomo ◽  
D. I. Perez ◽  
C. Gil ◽  
A. Martinez
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Potential Role ◽  
Glycogen Synthase ◽  
Pharmacological Therapy ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Lateral Sclerosis

scholarly journals Recent Advances on the Role of GSK3β in the Pathogenesis of Amyotrophic Lateral Sclerosis

2020 ◽  
Vol 10 (10) ◽  
pp. 675
Author(s):  
Hyun-Jun Choi ◽  
Sun Joo Cha ◽  
Jang-Won Lee ◽  
Hyung-Jun Kim ◽  
Kiyoung Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Protein Kinase ◽  
Molecular Mechanisms ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase 3 ◽  
Motor Neuron Degeneration ◽  
Neuron Degeneration ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a common neurodegenerative disease characterized by progressive motor neuron degeneration. Although several studies on genes involved in ALS have substantially expanded and improved our understanding of ALS pathogenesis, the exact molecular mechanisms underlying this disease remain poorly understood. Glycogen synthase kinase 3 (GSK3) is a multifunctional serine/threonine-protein kinase that plays a critical role in the regulation of various cellular signaling pathways. Dysregulation of GSK3β activity in neuronal cells has been implicated in the pathogenesis of neurodegenerative diseases. Previous research indicates that GSK3β inactivation plays a neuroprotective role in ALS pathogenesis. GSK3β activity shows an increase in various ALS models and patients. Furthermore, GSK3β inhibition can suppress the defective phenotypes caused by SOD, TDP-43, and FUS expression in various models. This review focuses on the most recent studies related to the therapeutic effect of GSK3β in ALS and provides an overview of how the dysfunction of GSK3β activity contributes to ALS pathogenesis.

scholarly journals Brief Review of the Role of Glycogen Synthase Kinase-3β in Amyotrophic Lateral Sclerosis

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Seong-Ho Koh ◽  
Wonki Baek ◽  
Seung H. Kim
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Therapeutic Strategy ◽  
Glycogen Synthase ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Glycogen Synthase Kinase ◽  
Diverse Range ◽  
Symptom Progression ◽  
Lateral Sclerosis

Glycogen synthase kinase-3β(GSK-3β) is known to affect a diverse range of biological functions controlling gene expression, cellular architecture, and apoptosis. GSK-3βhas recently been identified as one of the important pathogenic mechanisms in motor neuronal death related to amyotrophic lateral sclerosis (ALS). Therefore, the development of methods to control GSK-3βcould be helpful in postponing the symptom progression of ALS. Here we discuss the known roles of GSK-3βin motor neuronal cell death in ALS and the possibility of employing GSK-3βmodulators as a new therapeutic strategy.

scholarly journals Erratum to: A Crosstalk between the Biorhythms and Gatekeepers of Longevity: Dual Role of Glycogen Synthase Kinase-3

2021 ◽  
Vol 86 (5) ◽  
pp. 611-611
Author(s):  
Gregory A. Shilovsky ◽  
Tatyana S. Putyatina ◽  
Galina V. Morgunova ◽  
Alexander V. Seliverstov ◽  
Vasily V. Ashapkin ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Dual Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3

scholarly journals Possible Role of the Glycogen Synthase Kinase-3 Signaling Pathway in Trimethyltin-Induced Hippocampal Neurodegeneration in Mice

PLoS ONE ◽  
2013 ◽  
Vol 8 (8) ◽  
pp. e70356 ◽  
Author(s):  
Juhwan Kim ◽  
Miyoung Yang ◽  
Sung-Ho Kim ◽  
Jong-Choon Kim ◽  
Hongbing Wang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Glycogen Synthase ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Hippocampal Neurodegeneration

scholarly journals Deletion of Cardiomyocyte Glycogen Synthase Kinase-3 Beta (GSK-3β) Improves Systemic Glucose Tolerance with Maintained Heart Function in Established Obesity

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1120 ◽  
Author(s):  
Manisha Gupte ◽  
Prachi Umbarkar ◽  
Anand Prakash Singh ◽  
Qinkun Zhang ◽  
Sultan Tousif ◽  
...  
Keyword(s):  
Glucose Tolerance ◽  
Cardiac Function ◽  
Cardiac Dysfunction ◽  
Glycogen Synthase ◽  
Critical Role ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Total Period ◽  
Gsk 3Β

Obesity is an independent risk factor for cardiovascular diseases (CVD), including heart failure. Thus, there is an urgent need to understand the molecular mechanism of obesity-associated cardiac dysfunction. We recently reported the critical role of cardiomyocyte (CM) Glycogen Synthase Kinase-3 beta (GSK-3β) in cardiac dysfunction associated with a developing obesity model (deletion of CM-GSK-3β prior to obesity). In the present study, we investigated the role of CM-GSK-3β in a clinically more relevant model of established obesity (deletion of CM-GSK-3β after established obesity). CM-GSK-3β knockout (GSK-3βfl/flCre+/−) and controls (GSK-3βfl/flCre−/−) mice were subjected to a high-fat diet (HFD) in order to establish obesity. After 12 weeks of HFD treatment, all mice received tamoxifen injections for five consecutive days to delete GSK-3β specifically in CMs and continued on the HFD for a total period of 55 weeks. To our complete surprise, CM-GSK-3β knockout (KO) animals exhibited a globally improved glucose tolerance and maintained normal cardiac function. Mechanistically, in stark contrast to the developing obesity model, deleting CM-GSK-3β in obese animals did not adversely affect the GSK-3αS21 phosphorylation (activity) and maintained canonical β-catenin degradation pathway and cardiac function. As several GSK-3 inhibitors are in the trial to treat various chronic conditions, including metabolic diseases, these findings have important clinical implications. Specifically, our results provide critical pre-clinical data regarding the safety of GSK-3 inhibition in obese patients.

scholarly journals Identification of a novel selective and potent inhibitor of glycogen synthase kinase-3

2019 ◽  
Vol 317 (6) ◽  
pp. C1289-C1303 ◽  
Author(s):  
Mahboubeh S. Noori ◽  
Pooja M. Bhatt ◽  
Maria C. Courreges ◽  
Davoud Ghazanfari ◽  
Chaz Cuckler ◽  
...  
Keyword(s):  
Design Space ◽  
Potent Inhibitor ◽  
Glycogen Synthase ◽  
Selective Inhibition ◽  
Glycogen Synthase Kinase ◽  
Glycogen Synthase Kinase 3 ◽  
Cellular Functions ◽  
Starting Point ◽  
Potential Therapeutics

Glycogen synthase kinase-3 (GSK-3) is a multitasking protein kinase that regulates numerous critical cellular functions. Not surprisingly, elevated GSK-3 activity has been implicated in a host of diseases including pathological inflammation, diabetes, cancer, arthritis, asthma, bipolar disorder, and Alzheimer’s. Therefore, reagents that inhibit GSK-3 activity provide a means to investigate the role of GSK-3 in cellular physiology and pathophysiology and could become valuable therapeutics. Finding a potent inhibitor of GSK-3 that can selectively target this kinase, among over 500 protein kinases in the human genome, is a significant challenge. Thus there remains a critical need for the identification of selective inhibitors of GSK-3. In this work, we introduce a novel small organic compound, namely COB-187, which exhibits potent and highly selective inhibition of GSK-3. Specifically, this study 1) utilized a molecular screen of 414 kinase assays, representing 404 unique kinases, to reveal that COB-187 is a highly potent and selective inhibitor of GSK-3; 2) utilized a cellular assay to reveal that COB-187 decreases the phosphorylation of canonical GSK-3 substrates indicating that COB-187 inhibits cellular GSK-3 activity; and 3) reveals that a close isomer of COB-187 is also a selective and potent inhibitor of GSK-3. Taken together, these results demonstrate that we have discovered a region of chemical design space that contains novel GSK-3 inhibitors. These inhibitors will help to elucidate the intricate function of GSK-3 and can serve as a starting point for the development of potential therapeutics for diseases that involve aberrant GSK-3 activity.

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