Dual Inhibition of GSK3ß and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo.
Stem Cell Reports
; 12(3): 502-517, 2019 03 05.
Article
en En
| MEDLINE
| ID: mdl-30773488
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 GSK3ß is required to enhance the neuroprotective effects of CDK5 inhibition, which was confirmed using short hairpin RNA-mediated knockdown of CDK5 and GSK3ß. 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 GSK3ß in mediating the regulation of the neuronal cytoskeleton and that our hit compound LDC8 represents a promising starting point for neuroprotective drugs.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Citoesqueleto
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Quinasa 5 Dependiente de la Ciclina
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Glucógeno Sintasa Quinasa 3 beta
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Inflamación
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Degeneración Nerviosa
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Neuronas
Límite:
Animals
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Humans
Idioma:
En
Revista:
Stem Cell Reports
Año:
2019
Tipo del documento:
Article
País de afiliación:
Alemania