The Experts below are selected from a list of 11085 Experts worldwide ranked by ideXlab platform
Jesús Avila - One of the best experts on this subject based on the ideXlab platform.
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Understanding the relationship between GSK-3 and Alzheimer’s disease: a focus on how GSK-3 can modulate synaptic plasticity processes
Expert Review of Neurotherapeutics, 2013Co-Authors: Miguel Medina, Jesús AvilaAbstract:Originally discovered because of its role in the regulation of glucose metabolism, GSK-3 is now widely recognized as a crucial player in many cellular functions. Control of GSK-3 activity occurs by complex mechanisms that are each dependent upon specific signaling pathways. Furthermore, GSK-3 dysfunction has been linked to a number of pathologies, including Alzheimer’s disease (AD). In particular, the involvement of GSK-3 in several key pathophysiological pathways leading to AD and neurodegenerative diseases has placed this enzyme in a central position in this disorder. In this article, the authors will specifically focus on the role of this enzyme as a key regulator of synaptic plasticity and how alterations in the GSK-3 synaptic functions may be a major factor in AD and other neurodegenerative disorders.
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GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration
Frontiers in Molecular Neuroscience, 2011Co-Authors: Raquel Gómez-sintes, José J. Lucas, Félix Hernández, Jesús AvilaAbstract:Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.
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The Role of Glycogen Synthase Kinase-3 (GSK-3) in Alzheimer’s Disease
Alzheimer's Disease Pathogenesis-Core Concepts Shifting Paradigms and Therapeutic Targets, 2011Co-Authors: Miguel Ángel Medina, Jesús AvilaAbstract:Despite its initial discovery as one of five protein kinases activities found to phosphorylate glycogen synthase (GS) in fractioned extracts of rabbit skeletal muscle (Embi et al., 1980; Hemmings et al., 1981), Glycogen Synthase Kinase 3 (GSK-3) is by no means restricted to a role in glycogen metabolism. Indeed, the enzyme targets a wide variety of proteins involved in signalling, metabolism, structural proteins and a remarkable number of transcription factors and plays a far more pleiotropic role than first imagined (Woodgett, 2006). Genetic analyses and the use of selective inhibitors have shown that GSK-3 plays critical roles in development, metabolic homeostasis, neuronal growth and differentiation (Hur & Zhon, 2010), cell polarity, cell fate and apoptosis. Its unique position in modulating the function of a diverse series of proteins in combination with its association with a wide variety of human disorders, from neurodegenerative diseases, stroke, bipolar disorder to diabetes and cancer, has attracted significant attention to the protein both as a therapeutic target and as a means to understand the molecular basis of these disorders. In particular, the involvement of GSK-3 in several key pathophyisiological pathways leading to Alzheimer’s disease (AD) and neurodegenerative diseases has placed this enzyme in a central position in this disorder. Thus, GSK-3 has recently been proposed as a link between the two major pathological pathways in AD, amyloid and tau (Hernandez et al., 2010; Muyllaert et al., 2008) and even a “GSK-3 hypothesis of AD”, suggesting that GSK-3 might be a casual mediator of the disease, has been put forward (Hooper et al., 2008). This review will focus on describing the key role that GSK-3 plays in AD pathobiology and the use of GSK-3 inhibition as a potential therapeutic approach to treat this disease.
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Glycogen synthase kinase-3 (GSK-3) inhibitors for the treatment of Alzheimer's disease.
Current Pharmaceutical Design, 2010Co-Authors: Miguel Medina, Jesús AvilaAbstract:Abstract Originally discovered because of its role in the regulation of glucose metabolism, Glycogen Synthase Kinase-3 (GSK-3) it is now recognised as a crucial player in a diverse series of cellular processes involved in Alzheimer's disease (AD) pathology. Besides having been identified as the major tau protein kinase, GSK-3 mediates Aβ neurotoxicity, plays an essential role in synaptic plasticity and memory, might be involved in Aβ formation, and it has an important role in inflammation and neuronal survival, all key features of AD neuropathology. Moreover, AD was one of the earliest disorders linked to GSK-3 dysfunction. Thus, the discovery of small molecule GSK-3 inhibitors has attracted significant attention to the protein both as therapeutic target for the therapeutic intervention in neurodegenerative diseases as well as a means to understand the molecular basis of these disorders.
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Memantine Inhibits Calpain-Mediated Truncation of GSK-3 Induced by NMDA: Implications in Alzheimer's Disease
Journal of Alzheimer's Disease, 2009Co-Authors: Paloma Goñi-oliver, Jesús Avila, Félix HernándezAbstract:Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD.
Husseini K. Manji - One of the best experts on this subject based on the ideXlab platform.
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Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs
Neuropsychopharmacology, 2005Co-Authors: Todd D. Gould, Husseini K. ManjiAbstract:Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.
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AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test
International Journal of Neuropsychopharmacology, 2004Co-Authors: Todd D. Gould, Haim Einat, Ratan Bhat, Husseini K. ManjiAbstract:The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect is supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity. Taken together, these data support the hypothesis that lithium may exert its antidepressant effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may be useful for the treatment of bipolar disorder and depression.
James R. Woodgett - One of the best experts on this subject based on the ideXlab platform.
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The responses of neural stem cells to the level of GSK-3 depend on the tissue of origin
Biology Open, 2013Co-Authors: Tamara Holowacz, James R. Woodgett, Bradley W. Doble, Kevin F. Kelly, Tania O. Alexson, Brenda L.k. Coles, Derek Van Der KooyAbstract:Neural stem cells (NSCs) can be obtained from a variety of sources, but not all NSCs exhibit the same characteristics. We have examined how the level of glycogen synthase kinase-3 activity regulates NSCs obtained from different sources: the mouse embryonic striatum, embryonic hippocampus, and mouse ES cells. Growth of striatal NSCs is enhanced by mild inhibition of GSK-3 but not by strong inhibition that is accompanied by Wnt/TCF transcriptional activation. In contrast, the growth of hippocampal NSCs is enhanced by both mild inhibition of GSK-3 as well as stronger inhibition. Active Wnt/TCF signaling, which occurs normally in the embryonic hippocampus, is required for growth of neural stem and progenitor cells. In the embryonic striatal germinal zone, however, TCF signaling is normally absent and its activation inhibits growth of NSCs from this region. Using a genetic model for progressive loss of GSK-3, we find that primitive ES cell-derived NSCs resemble striatal NSCs. That is, partial loss of GSK-3 alleles leads to an increase in NSCs while complete ablation of GSK-3, and activation of TCF-signaling, leads to their decline. Furthermore, expression of dominant negative TCF-4 in the GSK-3-null background was effective in blocking expression of Wnt-response genes and was also able to rescue neuronal gene expression. These results reveal that GSK-3 regulates NSCs by divergent pathways depending on the tissue of origin. The responses of these neural precursor cells may be contingent on baseline Wnt/TCF signaling occurring in a particular tissue.
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GSK-3: Functional Insights from Cell Biology and Animal Models
Frontiers in Molecular Neuroscience, 2011Co-Authors: Oksana Kaidanovich-beilin, James R. WoodgettAbstract:Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded in mammals by two genes that generate two related proteins: GSK-3α and GSK-3β. GSK-3 is active in cells under resting conditions and is primarily regulated through inhibition or diversion of its activity. While GSK-3 is one of the few protein kinases that can be inactivated by phosphorylation, the mechanisms of GSK-3 regulation are more varied and not fully understood. Precise control appears to be achieved by a combination of phosphorylation, localization, and sequestration by a number of GSK-3-binding proteins. GSK-3 lies downstream of several major signaling pathways including the phosphatidylinositol 3’ kinase pathway, the Wnt pathway, Hedgehog signaling and Notch. Specific pools of GSK-3, which differ in intracellular localization, binding partner affinity and relative amount are differentially sensitized to several distinct signaling pathways and these sequestration mechanisms contribute to pathway insulation and signal specificity. Dysregulation of signaling pathways involving GSK-3 is associated with the pathogenesis of numerous neurological and psychiatric disorders and there are data suggesting GSK-3 isoform-selective roles in several of these. Here, we review the current knowledge of GSK-3 regulation and targets and discuss the various animal models that have been employed to dissect the functions of GSK-3 in brain development and function through the use of conventional or conditional knock-out mice as well as transgenic mice. These studies have revealed fundamental roles for these protein kinases in memory, behavior and neuronal fate determination and provide insights into possible therapeutic interventions.
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Molecular Mechanisms Underlying Pluripotency and Lineage Commitment – The Role of GSK-3
Embryonic Stem Cells - Basic Biology to Bioengineering, 2011Co-Authors: Bradley W. Doble, Kevin F. Kelly, James R. WoodgettAbstract:The highly related serine/threonine kinases GSK3┙ and GSK3┚ are transducers of Wnt/┚catenin, PI-3K, Notch and Hedgehog signalling pathways, placing them at the hub of key developmental and metabolic processes. There is accumulating evidence suggesting that GSK-3 inhibitors aid in the acquisition or sustenance of pluripotency in embryonic stem cells of mouse, rat and human origin. However, the mechanism through which GSK-3 inhibitors impart their effects is unclear due to the myriad cellular processes in which GSK-3 plays a role. Here, we review the studies that have examined the consequences of GSK-3 inhibition in pluripotent stem cells with a focus on key signalling pathways, which have been implicated in GSK-3 inhibitor-mediated effects.
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Does GSK-3 provide a shortcut for PI3K activation of Wnt signalling?
F1000 Medicine Reports, 2010Co-Authors: Daniel Voskas, Ling S. Ling, James R. WoodgettAbstract:Glycogen synthase kinase-3 (GSK-3) is a well-established downstream component of the pho- sphatidylinositol 3-kinase (PI3K) signalling pathway but is also a key enzyme in negatively regulating the canonical Wnt/b-catenin signalling pathway. Several recent studies argue that PKB (protein kinase B)- mediated inhibition of GSK-3 leads to b-catenin accumulation, but whether cross-talk actually exists between these two pathways is controversial. To elucidate the mechanisms of shared signalling components, further studies taking into account different components of the PI3K signalling pathway and different pools of GSK-3 or b-catenin are required.
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Inhibitory phosphorylation of GSK-3 by CaMKII couples depolarization to neuronal survival
Journal of Biological Chemistry, 2010Co-Authors: Bin Song, Zhihao Zheng, Yuying Zhang, Chong Wang, Yuan Chen, James R. Woodgett, Mingtao LiAbstract:Glycogen synthase kinase-3 (GSK-3) plays a critical role in neuronal apoptosis. The two mammalian isoforms of the kinase, GSK-3α and GSK-3β, are inhibited by phosphorylation at Ser-21 and Ser-9, respectively. Depolarization, which is vital for neuronal survival, causes both an increase in Ser-21/9 phosphorylation and an inhibition of GSK-3α/β. However, the role of GSK-3 phosphorylation in depolarization-dependent neuron survival and the signaling pathway contributing to GSK-3 phosphorylation during depolarization remain largely unknown. Using several approaches, we showed that both isoforms of GSK-3 are important for mediating neuronal apoptosis. Nonphosphorylatable GSK-3α/β mutants (S21A/S9A) promoted apoptosis, whereas a peptide encompassing Ser-9 of GSK-3β protected neurons in a phosphorylation-dependent manner; these results indicate a critical role for Ser-21/9 phosphorylation on depolarization-dependent neuron survival. We found that Ser-21/9 phosphorylation of GSK-3 was mediated by Ca2+/calmodulin-dependent protein kinase II (CaMKII) but not by Akt/PKB, PKA, or p90RSK. CaMKII associated with and phosphorylated GSK-3α/β. Furthermore, the pro-survival effect of CaMKII was mediated by GSK-3 phosphorylation and inactivation. These findings identify a novel Ca2+/calmodulin/CaMKII/GSK-3 pathway that couples depolarization to neuronal survival.
Todd D. Gould - One of the best experts on this subject based on the ideXlab platform.
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Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs
Neuropsychopharmacology, 2005Co-Authors: Todd D. Gould, Husseini K. ManjiAbstract:Despite many decades of clinical use, the therapeutic target of lithium remains uncertain. It is recognized that therapeutic concentrations of lithium, through competition with the similarly sized magnesium cation, inhibit the activity of select enzymes. Among these is glycogen synthase kinase-3 (GSK-3). Recent preclinical evidence, including biochemical, pharmacological, genetic, and rodent behavioral models, supports the hypothesis that inhibition of GSK-3 may represent a target for lithium's mood-stabilizing properties. Specifically, it has been demonstrated that lithium administration regulates multiple GSK-3 targets in vivo and that multiple additional classes of mood-stabilizing and antidepressant drugs regulate GSK-3 signaling. Pharmacological or genetic inhibition of GSK-3 results in mood stabilizer-like behavior in rodent models, and genetic association studies implicate GSK-3 as a possible modulator of particular aspects of bipolar disorder including response to lithium. Furthermore, numerous recent studies have provided a more complete understanding of GSK-3's role in diverse neurological processes strengthening the hypothesis that GSK-3 may represent a therapeutically relevant target of lithium. For example, GSK-3 is a primary regulator of neuronal survival, and cellular responses to glucocorticoids and estrogen may involve GSK-3-regulated pathways. While the preclinical evidence discussed in this review is encouraging, ultimate validation of GSK-3 as a therapeutically relevant target will require clinical trials of selective novel inhibitors. In this regard, as is discussed, there is a major effort underway to develop novel, specific, GSK-3 inhibitors.
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AR-A014418, a selective GSK-3 inhibitor, produces antidepressant-like effects in the forced swim test
International Journal of Neuropsychopharmacology, 2004Co-Authors: Todd D. Gould, Haim Einat, Ratan Bhat, Husseini K. ManjiAbstract:The mechanism by which lithium exerts either its anti-manic or antidepressant effects remains to be fully elucidated. Although lithium inhibits the enzyme glycogen synthase kinase-3 (GSK-3) at concentrations that are relevant for treatment of bipolar disorder, it is unclear whether GSK-3-related mechanisms are responsible for its therapeutic effects in the treatment of this disease. We report that AR-A014418 (a selective GSK-3 inhibitor) induces behavioural changes that are consistent with the effects of antidepressant medications. Subacute intraperitoneal injections of AR-A014418 reduced immobility time in rats exposed to the forced swim test, a well-established model for antidepressant efficacy. In addition, the specificity of this effect is supported by our finding that AR-A014418 decreased spontaneous as well as amphetamine-induced activity. Taken together, these data support the hypothesis that lithium may exert its antidepressant effects through inhibition of GSK-3, and that novel small-molecule GSK-3 inhibitors may be useful for the treatment of bipolar disorder and depression.
Félix Hernández - One of the best experts on this subject based on the ideXlab platform.
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GSK-3 Mouse Models to Study Neuronal Apoptosis and Neurodegeneration
Frontiers in Molecular Neuroscience, 2011Co-Authors: Raquel Gómez-sintes, José J. Lucas, Félix Hernández, Jesús AvilaAbstract:Increased GSK-3 activity is believed to contribute to the etiology of chronic disorders like Alzheimer’s disease (AD), schizophrenia, diabetes, and some types of cancer, thus supporting therapeutic potential of GSK-3 inhibitors. Numerous mouse models with modified GSK-3 have been generated in order to study the physiology of GSK-3, its implication in diverse pathologies and the potential effect of GSK-3 inhibitors. In this review we have focused on the relevance of these mouse models for the study of the role of GSK-3 in apoptosis. GSK-3 is involved in two apoptotic pathways, intrinsic and extrinsic pathways, and plays opposite roles depending on the apoptotic signaling process that is activated. It promotes cell death when acting through intrinsic pathway and plays an anti-apoptotic role if the extrinsic pathway is occurring. It is important to dissect this duality since, among the diseases in which GSK-3 is involved, excessive cell death is crucial in some illnesses like neurodegenerative diseases, while a deficient apoptosis is occurring in others such as cancer or autoimmune diseases. The clinical application of a classical GSK-3 inhibitor, lithium, is limited by its toxic consequences, including motor side effects. Recently, the mechanism leading to activation of apoptosis following chronic lithium administration has been described. Understanding this mechanism could help to minimize side effects and to improve application of GSK-3 inhibitors to the treatment of AD and to extend the application to other diseases.
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Memantine Inhibits Calpain-Mediated Truncation of GSK-3 Induced by NMDA: Implications in Alzheimer's Disease
Journal of Alzheimer's Disease, 2009Co-Authors: Paloma Goñi-oliver, Jesús Avila, Félix HernándezAbstract:Deregulation of glycogen synthase kinase-3 (GSK-3) activity is believed to play a key role in the pathogenesis of Alzheimer's disease (AD). GSK-3 activity is regulated by phosphorylation and through interaction with GSK-3-binding proteins. Previously, we demonstrated that calpain activation produces a truncation of GSK-3. In this study, we show that calpain-mediated GSK-3 truncation, induced by N-methyl-D-aspartic acid (NMDA), depends on extracellular calcium. Primary cultures of cortical neurons treated with NMDA reduce GSK-3 levels up to 75%, although the truncated form of GSK-3 does not accumulate, suggesting that a short-lived product is formed. The data obtained with human AD samples suggest that, although a great variability exists at least in postmortem samples, truncated GSK-3 does not accumulate. However, memantine, a non-competitive NMDA receptor which has been approved for the treatment of moderate to severe AD, is able to inhibit GSK-3 truncation induced by NMDA in primary cultures of cortical neurons in a dose-dependent manner. Thus, memantine modulates GSK-3 signaling, which might explain its protective role in AD. Overall, our data reinforces the important relationship between NMDA receptors and GSK-3 and their involvement as one of the first steps in neurodegenerative diseases such as AD.
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Calpain-mediated truncation of GSK-3 in post-mortem brain samples
Journal of Neuroscience Research, 2009Co-Authors: Paloma Goñi-oliver, Jesús Avila, Félix HernándezAbstract:GSK-3 activity can be regulated by phosphorylation and through interaction with GSK-3-binding proteins. In addition, we have recently demonstrated that calpain activation produces a truncation of GSK-3 that removes the N-terminal inhibitory domain (Goni-Oliver et al. [2007] J. Biol. Chem. 282:22406). Given that calpain is involved in post-mortem proteolysis in brain samples, the objective of this investigation was to test whether GSK-3 is truncated in post-mortem samples. To achieve this objective, we first investigated the degradation of GSK-3 during different post-mortem intervals in mouse brains and found that the conversion of GSK-3 to proteolytic fragments of 40 and 30 kDa takes place in a way similar that of to p35-CDK-5 subunit and spectrin, two well-known calpain substrates. In addition, we demonstrated that this truncation is mediated by calpain, insofar as pretreatment with MDL 28170, a permeable blood–brain barrier calpain inhibitor, partially inhibited that degradation. When human brain extracts were exposed to calcium, GSK-3 was truncated, generating two fragments of approximately 40 and 30 kDa, a proteolytic process that was inhibited by calpeptin, a specific calpain inhibitor. Thus, this is the first report of calcium-dependent truncation of human GSK-3. These data demonstrate that control samples with similar post-mortem delay are essential to interpret correctly the changes observed in GSK-3 levels in human post-mortem brain, especially when studying human neurodegenerative diseases. © 2008 Wiley-Liss, Inc.
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GSK-3 inhibitors for Alzheimer’s disease
Expert Review of Neurotherapeutics, 2007Co-Authors: Jesús Avila, Félix HernándezAbstract:Glycogen synthase kinase (GSK)-3 has been proposed as the link between the two histopathological hallmarks of Alzheimer’s disease, the extracellular senile plaques made of β-amyloid and the intracellular neurofibrillary tangles made of hyperphosphorylated tau. Thus, GSK-3 is one of the main tau kinases and it modifies several sites of tau protein present in neurofibrillary tangles. Furthermore, GSK-3 is able to modulate the generation of β-amyloid as well as to respond to this peptide. The use of several transgenic models overexpressing GSK-3 has been associated with neuronal death, tau hyperphosphorylation and a decline in cognitive performance. Lithium, a widely used drug for affective disorders, inhibits GSK-3 at therapeutically relevant concentrations and has been demonstrated to prevent tau phosphorylation. In this review, we summarize all these data and discuss the potential of GSK-3 inhibitors for Alzheimer’s disease therapy, as well as some of their potential problems.
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N-terminal Cleavage of GSK-3 by Calpain A NEW FORM OF GSK-3 REGULATION
Journal of Biological Chemistry, 2007Co-Authors: Paloma Goñi-oliver, José J. Lucas, Jesús Avila, Félix HernándezAbstract:Abstract Although GSK-3 activity can be regulated by phosphorylation and through interaction with GSK-3-binding proteins, here we describe N-terminal proteolysis as a novel way to regulate GSK-3. When brain extracts were exposed to calcium, GSK-3 was truncated, generating two fragments of ∼40 and 30 kDa, a proteolytic process that was inhibited by specific calpain inhibitors. Interestingly, instead of inhibiting this enzyme, GSK-3 truncation augmented its kinase activity. When we digested recombinant GSK-3α and GSK-3β protein with calpain, each isoform was cleaved differently, yet the truncated GSK-3 isoforms were still active kinases. We also found that lithium, a GSK-3 inhibitor, inhibits full-length and cleaved GSK-3 isoforms with the same IC50 value. Calpain removed the N-terminal ends of His-tagged GSK-3 isoenzymes, and exposing cultured cortical neurons with ionomycin, glutamate, or N-methyl-d-aspartate led to the truncation of GSK-3. This truncation was blocked by the calpain inhibitor calpeptin, at the same concentration at which it inhibits calpain-mediated cleavage of NMDAR-2B and of p35 (the regulatory subunit of CDK5). Together, our data demonstrate that calpain activation produces a truncation of GSK-3 that removes an N-terminal inhibitory domain. Furthermore, we show that GSK-3α and GSK-3β isoenzymes have a different susceptibility to this cleavage, suggesting a means to specifically regulate these isoenzymes. These data provide the first direct evidence that calpain promotes GSK-3 truncation in a way that has implications in signal transduction, and probably in pathological disorders such as Alzheimer disease.
