ZFIN ID: ZDB-PUB-190219-7
Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo
Reinhardt, L., Kordes, S., Reinhardt, P., Glatza, M., Baumann, M., Drexler, H.C.A., Menninger, S., Zischinsky, G., Eickhoff, J., Fröb, C., Bhattarai, P., Arulmozhivarman, G., Marrone, L., Janosch, A., Adachi, K., Stehling, M., Anderson, E.N., Abo-Rady, M., Bickle, M., Pandey, U.B., Reimer, M.M., Kizil, C., Schöler, H.R., Nussbaumer, P., Klebl, B., Sterneckert, J.L.
Date: 2019
Source: Stem Cell Reports   12(3): 502-517 (Journal)
Registered Authors: Bhattarai, Prabesh, Kizil, Caghan, Reimer, Michell M.
Keywords: ALS, CDK5, GSK3β, induced pluripotent stem cells, neurodegeneration, neuroinflammation, stem cell-based phenotypic screening
MeSH Terms:
  • Alzheimer Disease/drug therapy
  • Alzheimer Disease/metabolism
  • Animals
  • Cyclin-Dependent Kinase 5/metabolism*
  • Cytoskeleton/drug effects
  • Cytoskeleton/metabolism*
  • Glycogen Synthase Kinase 3 beta/metabolism*
  • Humans
  • Inflammation/drug therapy
  • Inflammation/metabolism*
  • Microtubules/drug effects
  • Microtubules/metabolism
  • Nerve Degeneration/drug therapy
  • Nerve Degeneration/metabolism*
  • Neurites/drug effects
  • Neurites/metabolism
  • Neurons/drug effects
  • Neurons/metabolism*
  • Neuroprotective Agents/pharmacology
  • Phosphorylation/drug effects
  • Signal Transduction/drug effects
  • Zebrafish/metabolism
PubMed: 30773488 Full text @ Stem Cell Reports
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.