ArticleStem cell reports2019
Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo.
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Article in Stem cell reports, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37citing papers in PubMed
5.9field-weighted citation impact, top 3% of its field
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37 citing papers in PubMed, 68 citations in OpenAlex.
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- GSK3: A potential target and pending issues for treatment of Alzheimer's disease.CNS neuroscience & therapeutics · 2024Review
- Ketamine impairs growth cone and synaptogenesis in human GABAergic projection neurons via GSK-3β and HDAC6 signaling.Molecular psychiatry · 2024Article
- Unveiling Potential Neurotoxic Mechansisms: Pb-Induced Activation of CDK5-p25 Signaling Axis in Alzheimer's Disease Development, Emphasizing CDK5 Inhibition and Formation of Toxic p25 Species.Molecular neurobiology · 2024Article
- Screening Techniques for Drug Discovery in Alzheimer's Disease.ACS omega · 2024Review
- Regulation of Microtubule Stability in Pulmonary Microvascular Endothelial Cells in Rats with Severe Acute Pancreatitis: Qingyi Decoction is a Potential CDK5 Inhibitor.Journal of inflammation research · 2024Article
- Exploring the role of COX-2 in Alzheimer's disease: Potential therapeutic implications of COX-2 inhibitors.Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society · 2023Review
- Nerve growth factor receptor (Ngfr) induces neurogenic plasticity by suppressing reactive astroglial Lcn2/Slc22a17 signaling in Alzheimer's disease.NPJ Regenerative medicine · 2023Article
- Cdk5 and aberrant cell cycle activation at the core of neurodegeneration.Neural regeneration research · 2023Review
- Analyzing the ER stress response in ALS patient derived motor neurons identifies druggable neuroprotective targets.Frontiers in cellular neuroscience · 2023Article
- miR-196a enhances polymerization of neuronal microfilaments through suppressing IMP3 and upregulating IGF2 in Huntington's disease.Molecular therapy. Nucleic acids · 2022Article
- Unraveling axonal mechanisms of traumatic brain injury.Acta neuropathologica communications · 2022Article
- BmCDK5 Affects Cell Proliferation and Cytoskeleton Morphology by Interacting with BmCNN inInsects · 2022Article
- FMNL2 regulates gliovascular interactions and is associated with vascular risk factors and cerebrovascular pathology in Alzheimer's disease.Acta neuropathologica · 2022Article
- The Brilliance of the Zebrafish Model: Perception on Behavior and Alzheimer's Disease.Frontiers in behavioral neuroscience · 2022Review
Corrections and comments
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Authors and funding
26 authors at 7 institutions in 2 countries.
Lydia ReinhardtTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Susanne KordesDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; Lead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Peter ReinhardtTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Michael GlatzaTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Matthias BaumannLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Hannes C A DrexlerBioanalytical Mass Spectrometry, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Sascha MenningerLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Gunther ZischinskyLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Jan EickhoffLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Claudia FröbTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany.
Prabesh BhattaraiTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany.
Guruchandar ArulmozhivarmanTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany.
Lara MarroneTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany.
Antje JanoschMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Kenjiro AdachiDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Martin StehlingDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany.
Eric N AndersonDepartment of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA.
Masin Abo-RadyTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany.
Marc BickleMax Planck Institute of Molecular Cell Biology and Genetics, 01307 Dresden, Germany.
Udai Bhan PandeyDepartment of Pediatrics, Division of Child Neurology, Children's Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA; Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA 15261, USA; Department of Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Michell M ReimerTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany.
Caghan KizilTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; German Center for Neurodegenerative Diseases (DZNE) within the Helmholtz Association, Tatzberg 41, 01307 Dresden, Germany.
Hans R SchölerDepartment of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany; University of Münster, Medical Faculty, Domagkstrasse 3, 48149 Münster, Germany.
Peter NussbaumerLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Bert KleblLead Discovery Center GmbH, Otto-Hahn-Strasse 15, 44227 Dortmund, Germany.
Jared L SterneckertTechnische Universität Dresden, DFG-Research Center for Regenerative Therapies Dresden (CRTD), Fetscherstrasse 105, 01307 Dresden, Germany; Department of Cell and Developmental Biology, Max Planck Institute for Molecular Biomedicine, Röntgenstrasse 20, 48149 Münster, Germany. Electronic address: jared.sterneckert@tu-dresden.de.
Technische Universität Dresden · DELead Discovery Center (Germany) · DEMax Planck Institute for Molecular Biomedicine · DEMax Planck Institute of Molecular Cell Biology and Genetics · DEUniversity of Pittsburgh · USGerman Center for Neurodegenerative Diseases · DEUniversity of Münster · DE
Funding
Pharmaco Response Signatures and Disease MechanismU54HL127365 · NHLBI · HARVARD MEDICAL SCHOOL · PI SORGER, PETER KARL · 2014 to 2019
$13.1MPharmaco Response Signatures and Disease MechanismU54HG006097 · NHGRI · HARVARD MEDICAL SCHOOL · PI MITCHISON, TIMOTHY J, SORGER, PETER KARL · 2010 to 2013
$9.7MTraining in the Neurobiology of Neurological DiseaseT32NS086749 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI Omar El Gharbawie, REBECCA P SEAL · 2014 to 2026
$4.8MCellular and Molecular Mechanisms of FUS-related Amyotrophic Lateral SclerosisR01NS081303 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI PANDEY, UDAI B · 2013 to 2023
$3.6MNuclear export inhibition as a novel therapeutic target for C9ORF72 ALS/FTDR21NS098379 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DONNELLY, CHRISTOPHER JAMES, PANDEY, UDAI B · 2017 to 2018
$429kMolecular mechanisms of C9orf72 and Matrin 3 interaction in ALSR21NS100055 · NINDS · UNIVERSITY OF PITTSBURGH AT PITTSBURGH · PI DONNELLY, CHRISTOPHER JAMES, PANDEY, UDAI B · 2017 to 2018
$427kDrosophila models for ubiquilin-associated ALSR21NS101661 · NINDS · UNIVERSITY OF WISCONSIN-MADISON · PI PANDEY, UDAI B, TIBBETTS, RANDAL SCOT · 2017 to 2018
$422kNHGRI NIH HHS U54 HG006097NHLBI NIH HHS U54 HL127365NINDS NIH HHS R01 NS081303NINDS NIH HHS R21 NS098379NINDS NIH HHS R21 NS100055NINDS NIH HHS R21 NS101661NINDS NIH HHS T32 NS086749
Abstract
Neuroinflammation is a hallmark of neurological disorders and is accompanied by the production of neurotoxic agents such as nitric oxide. We used stem cell-based phenotypic screening and identified small molecules that directly protected neurons from neuroinflammation-induced degeneration. We demonstrate that inhibition of CDK5 is involved in, but not sufficient for, neuroprotection. Instead, additional inhibition of GSK3β is required to enhance the neuroprotective effects of CDK5 inhibition, which was confirmed using short hairpin RNA-mediated knockdown of CDK5 and GSK3β. Quantitative phosphoproteomics and high-content imaging demonstrate that neurite degeneration is mediated by aberrant phosphorylation of multiple microtubule-associated proteins. Finally, we show that our hit compound protects neurons in vivo in zebrafish models of motor neuron degeneration and Alzheimer's disease. Thus, we demonstrate an overlap of CDK5 and GSK3β in mediating the regulation of the neuronal cytoskeleton and that our hit compound LDC8 represents a promising starting point for neuroprotective drugs.
Indexed as
Alzheimer DiseaseAnimalsCyclin-Dependent Kinase 5CytoskeletonGlycogen Synthase Kinase 3 betaHumansInflammationMicrotubulesNerve DegenerationNeuritesNeuronsNeuroprotective AgentsPhosphorylationSignal TransductionZebrafishCDK5 protein, humanCyclin-Dependent Kinase 5Glycogen Synthase Kinase 3 betaNeuroprotective AgentsALSCDK5GSK3βinduced pluripotent stem cellsneurodegenerationneuroinflammationstem cell-based phenotypic screening
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