Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo.

First Authors Lydia Reinhardt
Authors Lydia Reinhardt, Susanne Kordes, Peter Reinhardt, Michael Glatza, Michael Baumann, Hannes C A Drexler, Sascha Menninger, Gunther Zischinsky, Jan Eickhoff, Claudia Fröb, Prabesh Bhattarai, Guruchandar Arulmozhivarman, Lara Marrone, Antje Janosch, Kenjiro Adachi, Martin Stehling, Eric D Anderson, Masin Abo-Rady, Marc Bickle, Udai Pandey, Michell M Reimer, Caghan Kizil, Hans R Schöler, Peter Nussbaumer, Bert Klebl, Jared Sterneckert
Corresponding Authors Jared Sterneckert
Last Authors Jared Sterneckert
Journal Name Stem cell reports (Stem Cell Reports)
Volume 12
Issue 3
Page Range 502-517
PubMed ID 30773488
WebOfScience Link WOS:000460407800007
Open Access true
Print Publication Date 2019-03-05
Online Publication Date
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.
Cover Image
Affiliated With Technology Development Studio TDS
Selected By
Acknowledged Services
Publication Status Published
Edoc Link
Sfx Link
DOI 10.1016/j.stemcr.2019.01.015
Display Publisher Download Only false
Visible On MPI-CBG Website true
PDF Downloadable true
Created By thuem
Added Date 2019-03-07
Last Edited By verhegge
Last Edited Date 2019-03-25 10:54:18.515
Library ID 7348
Document ID
Entry Complete true
eDoc Compliant true
Include in Edoc Report true
Author Affiliations Complete false