A Combined Cell-Worm Approach to Search for Compounds Counteracting the Toxicity of Tau Oligomers In Vivo
| Autor: | Carmina Natale, Maria Monica Barzago, Luca Colnaghi, Ada De Luigi, Franca Orsini, Luana Fioriti, Luisa Diomede |
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| Rok vydání: | 2022 |
| Předmět: |
Organic Chemistry
tauopathy proteotoxicity tau Proteins General Medicine tetracyclines Catalysis tau protein Computer Science Applications pharmacology_toxicology Inorganic Chemistry HEK293 Cells Tauopathies Doxycycline oligomers C. elegans Animals Humans Physical and Theoretical Chemistry Caenorhabditis elegans Molecular Biology Spectroscopy |
| Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 19; Pages: 11277 |
| ISSN: | 1422-0067 |
| Popis: | A clear relationship between the tau assemblies and toxicity has still to be established. To correlate the tau conformation with its proteotoxic effect in vivo, we developed an innovative cell-worm-based approach. HEK293 cells expressing tau P301L under a tetracycline-inducible system (HEK T-Rex) were employed to produce different tau assemblies whose proteotoxic potential was evaluated using C. elegans. Lysates from cells induced for five days significantly reduced the worm's locomotor activity. This toxic effect was not related to the total amount of tau produced by cells or to its phosphorylation state but was related to the formation of multimeric tau assemblies, particularly tetrameric ones. We investigated the applicability of this approach for testing compounds acting against oligomeric tau toxicity, using doxycycline (Doxy) as a prototype drug. Doxy affected tau solubility and promoted the disassembly of already formed toxic aggregates in lysates of cells induced for five days. These effects translated into a dose-dependent protective action in C. elegans. These findings confirm the validity of the combined HEK T-Rex cells and the C. elegans-based approach as a platform for pharmacological screening. |
| Databáze: | OpenAIRE |
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