期刊
STEM CELL REPORTS
卷 12, 期 3, 页码 502-517出版社
CELL PRESS
DOI: 10.1016/j.stemcr.2019.01.015
关键词
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资金
- DFG [DFG FZT 111, DFG EXC 168]
- Max Planck Society
- BMBF [01EK1606A]
- European Union [643417]
- Bundesministerium fur Bildung und Forschung [01ED1601B]
- Germany, Bundesministerium fur Bildung und Forschung
- Israel, Ministry of Health
- Italy, Ministero dell'Istruzione, dell'Universitae della Ricerca
- Sweden, Swedish Research Council
- Switzerland, Swiss National Science Foundation
- NIH [U54 HG006097, U54 HL127365]
- Hans and Ilse Breuer Stiftung
- National Institutes of Health [NS081303, NS101661, NS100055, NS098379]
- Pennsylvania Tobacco Research grant
- Robert Packard Center for ALS Research at Johns Hopkins
- ALS Association
- Muscular Dystrophy Association
- German Center for Neurodegenerative Diseases (DZNE)
- Helmholtz Association [VH-NG-1021]
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 GSK3 beta is required to enhance the neuroprotective effects of CDK5 inhibition, which was confirmed using short hairpin RNA-mediated knockdown of CDK5 and GSK3 beta. 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 GSK3 beta in mediating the regulation of the neuronal cytoskeleton and that our hit compound LDC8 represents a promising starting point for neuroprotective drugs.
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