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

Choi, Hyun-Jun; Joo, Sun Hyung; Lee, Jangwon; Kim, Ki‐Young

doi:10.3390/brainsci10100675

Cited by 27 publications

(16 citation statements)

References 120 publications

(165 reference statements)

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“…We focus on the modulation of GSK-3β, as it is recognized as one of the main kinases involved in aberrant phosphorylation of TDP-43 [5]. Moreover, alterations in GSK-3β expression and activity have been described in postmortem spinal cords and frontal and temporal cortex of ALS patients [7][8][9][10].…”

Section: Discussionmentioning

confidence: 99%

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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Section: Discussionmentioning

confidence: 99%

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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“…Abnormal regulation of GSK-3β has been linked to both the onset and progression of different chronic conditions such as diabetes, cancer, neurodegenerative (e.g., AD, PD, ALS), and behavioral diseases (e.g., bipolar disorder (BD), major depression (MD), schizophrenia). In CNS-related disorders, aberrant GSK-3β activity is associated with the dysregulation of different proteins, namely microtubule-associated protein τ, presenilins, amyloid precursor protein (APP), collapsin response mediator proteins, components of the Wnt signaling pathway, β-catenin, and heat shock proteins [37]. Moreover, several lines of evidence have reported GSK-3β as a mediator of neuroinflammatory processes.…”

Section: Gsk-3βmentioning

confidence: 99%

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Demuro

Martino

Ortega

et al. 2021

IJMS

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Protein kinases (PKs) have been recognized as central nervous system (CNS)-disease-relevant targets due to their master regulatory role in different signal transduction cascades in the neuroscience space. Among them, GSK-3β, FYN, and DYRK1A play a crucial role in the neurodegeneration context, and the deregulation of all three PKs has been linked to different CNS disorders with unmet medical needs, including Alzheimer’s disease (AD), Parkinson’s disease (PD), frontotemporal lobar degeneration (FTLD), and several neuromuscular disorders. The multifactorial nature of these diseases, along with the failure of many advanced CNS clinical trials, and the lengthy approval process of a novel CNS drug have strongly limited the CNS drug discovery. However, in the near-decade from 2010 to 2020, several computer-assisted drug design strategies have been combined with synthetic efforts to develop potent and selective GSK-3β, FYN, and DYRK1A inhibitors as disease-modifying agents. In this review, we described both structural and functional aspects of GSK-3β, FYN, and DYRK1A and their involvement and crosstalk in different CNS pathological signaling pathways. Moreover, we outlined attractive medicinal chemistry approaches including multi-target drug design strategies applied to overcome some limitations of known PKs inhibitors and discover improved modulators with suitable blood–brain barrier (BBB) permeability and drug-like properties.

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“…This choice stemmed from the notion that GSK3β activation or inhibition reduces or increases VAPB-PTPIP51 interaction, respectively [ 59 ], although the molecular mechanism of such regulation is still unclear. Importantly, the perturbation of GSK3β activity was also implicated in the pathogenesis of ALS and many other neurodegenerative disorders [ 94 , 95 , 96 ]. For the first time to our knowledge, here, we demonstrated that TDP-43 down-regulation induces both an increased expression and a higher activation (i.e., reduced phosphorylation in Ser9) of GSK3β, allowing us to speculate that this pathway may significantly contribute to the reported reduction in ER–mitochondria tethering after TDP-43 silencing.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Endoplasmic Reticulum–Mitochondria Tethering and Ca2+ Fluxes by TDP-43 via GSK3β

Peggion

Massimino

Bonadio

et al. 2021

IJMS

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Mitochondria–ER contacts (MERCs), tightly regulated by numerous tethering proteins that act as molecular and functional connections between the two organelles, are essential to maintain a variety of cellular functions. Such contacts are often compromised in the early stages of many neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). TDP-43, a nuclear protein mainly involved in RNA metabolism, has been repeatedly associated with ALS pathogenesis and other neurodegenerative diseases. Although TDP-43 neuropathological mechanisms are still unclear, the accumulation of the protein in cytoplasmic inclusions may underlie a protein loss-of-function effect. Accordingly, we investigated the impact of siRNA-mediated TDP-43 silencing on MERCs and the related cellular parameters in HeLa cells using GFP-based probes for MERCs quantification and aequorin-based probes for local Ca2+ measurements, combined with targeted protein and mRNA profiling. Our results demonstrated that TDP-43 down-regulation decreases MERCs density, thereby remarkably reducing mitochondria Ca2+ uptake after ER Ca2+ release. Thorough mRNA and protein analyses did not highlight altered expression of proteins involved in MERCs assembly or Ca2+-mediated ER–mitochondria cross-talk, nor alterations of mitochondrial density and morphology were observed by confocal microscopy. Further mechanistic inspections, however, suggested that the observed cellular alterations are correlated to increased expression/activity of GSK3β, previously associated with MERCs disruption.

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

Cited by 27 publications

References 120 publications

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

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

GSK-3β, FYN, and DYRK1A: Master Regulators in Neurodegenerative Pathways

Regulation of Endoplasmic Reticulum–Mitochondria Tethering and Ca2+ Fluxes by TDP-43 via GSK3β

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