Glycogen Synthase Kinase-3β Expression and Phosphorylation in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

González‐Muñoz, Miguel; Rodríguez-Mahillo, Ana I.; Gil, Carmen; Morán, Yolanda; Moneo, Ignacio; Martı́nez, Ana; Mora, Jesús

doi:10.9734/bjmmr/2014/5578

Cited by 3 publications

(2 citation statements)

References 25 publications

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“…In ALS patients, an up‐regulation of GSK‐3 in spinal cord and frontal and temporal cortex has been described (Yang, Leystra‐Lantz, & Strong, 2008). Furthermore, GSK‐3 is also expressed in peripheral blood mononuclear cells of patients with ALS and these levels of active kinase are directly related to clinical symptoms (González‐Muñoz et al, 2013). Thus, inhibitors of GSK‐3 have been proposed as a new therapy for ALS in the last decade (Palomo, Perez, Gil, & Martinez, 2011).…”

Section: Protein Kinase Inhibitors In Clinical Trials For Alsmentioning

confidence: 99%

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Palomo

Nozal

Rojas-Prats

et al. 2020

British J Pharmacology

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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that causes the progressive loss of motoneurons and, unfortunately, there is no effective treatment for this disease. Interconnecting multiple pathological mechanisms are involved in the neuropathology of this disease, including abnormal aggregation of proteins, neuroinflammation and dysregulation of the ubiquitin proteasome system. Such complex mechanisms, together with the lack of reliable animal models of the disease have hampered the development of drugs for this disease. Protein kinases, a key pharmacological target in several diseases, have been linked to ALS as they play a central role in the pathology of many diseases. Therefore several inhibitors are being currently trailed for clinical proof of concept in ALS patients. In this review, we examine the recent literature on protein kinase inhibitors currently in pharmaceutical development for this diseaseas future therapy for AS together with their involvement in the pathobiology of ALS. LINKED ARTICLES This article is part of a themed issue on Neurochemistry in Japan. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.6/issuetoc

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Section: Protein Kinase Inhibitors In Clinical Trials For Alsmentioning

confidence: 99%

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Palomo

Nozal

Rojas-Prats

et al. 2020

British J Pharmacology

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“…Intriguingly, GSK3β has been observed to be overexpressed in non-neural cells of ALS patients, suggesting its potential involvement in the disease’s progression. [74] Further, GSK3β hyperactivity has been confirmed as a causative factor in disease pathogenesis, while its inhibition is a potential therapeutic avenue. [75,76] Our results demonstrate that active NaBC1 triggers intracellular signaling via activation of IGF-Akt-mTOR axis.…”

Section: Resultsmentioning

confidence: 99%

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and generate neuroprotection in the SOD1^G93Amouse model of ALS via activation of the IGF–Akt–mTOR axis pathway

Rodriguez-Romano,

Gonzalez-Valdivieso,

Moreno-Martinez

et al. 2023

Preprint

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Amyotrophic Lateral Sclerosis (ALS) is the most frequent and fatal condition that causes motor neurons loss and skeletal muscle paralysis. Although ALS is associated with mutations in over 40 genes, its etiology remains elusive without a cure or effective treatment. Historically considered the prototype of motor neuron diseases, ALS is defined today as a multisystem disorder that presents several changes in non-neuronal cell types, such as pathological changes in muscle occurring before disease onset and independent from motor neuron degeneration (dying back hypothesis). We based in the hypothesis that skeletal muscle may have an active contribution to disease pathology and thus we consider skeletal muscle tissue as a therapeutic target for ALS.In previous works we have demonstrated that borate (B) transporter NaBC1 (encoded bySLC4A11gene), after activation co-localize with integrins and growth factor receptors producing a functional cluster that synergistically enhances crosstalk mechanisms accelerating muscle repair. In this work we aimed to study the effects of B in a SOD1 mouse model of ALS targeting muscle. We have engineered and characterized injectable alginate-based hydrogels with controlled local borax-release for an effective activation of NaBC1in vivo. Treated mice presented improved motor function and extended survival that was correlated with an enhanced muscle repair response inducing a reduction in muscle atrophy and inflammation. Interestingly, the activation of muscle repair mechanisms at local level, produced a retrograde neuroprotection by motor neuron preservation and reduction in neuro-inflammation. Altogether, this work presents evidence supporting the involvement of muscle tissue in ALS pathology, reinforcing skeletal muscle as a primary target to develop new therapies for ALS. We propose a novel strategy based on NaBC1 activation for ALS muscle regeneration.

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Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis

Martínez-González

Gonzalo‐Consuegra

Gómez‐Almería

et al. 2021

IJMS

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Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3β is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3β inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3β activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.

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Glycogen Synthase Kinase-3β Expression and Phosphorylation in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

Abstract: Aims: To quantify total glycogen synthase kinase (GSK)-3β and GSK-3β phosphorylated at serine 9 in the peripheral blood mononuclear cells from Amyotrophic Lateral Sclerosis (ALS) patients and to assess if GSK-3β could be a biomarker for ALS.

Cited by 3 publications

References 25 publications

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and generate neuroprotection in the SOD1^G93Amouse model of ALS via activation of the IGF–Akt–mTOR axis pathway

Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis

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Glycogen Synthase Kinase-3β Expression and Phosphorylation in Peripheral Blood Mononuclear Cells of Patients with Amyotrophic Lateral Sclerosis

Abstract: Aims: To quantify total glycogen synthase kinase (GSK)-3β and GSK-3β phosphorylated at serine 9 in the peripheral blood mononuclear cells from Amyotrophic Lateral Sclerosis (ALS) patients and to assess if GSK-3β could be a biomarker for ALS.

Cited by 3 publications

References 25 publications

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Protein kinase inhibitors for amyotrophic lateral sclerosis therapy

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and generate neuroprotection in the SOD1G93Amouse model of ALS via activation of the IGF–Akt–mTOR axis pathway

Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3β as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis

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Product

Resources

About

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, modulate inflammation, and generate neuroprotection in the SOD1^G93Amouse model of ALS via activation of the IGF–Akt–mTOR axis pathway