Prolonged tau clearance and stress vulnerability rescue by pharmacological activation of autophagy in tauopathy neurons
| Autor: | Stephen J. Haggarty, Bradford C. Dickerson, Diane Lucente, Dean G. Brown, Nicholas J. Brandon, Tanguy Jamier, Ian Gurrell, Ghata Nandi, Sharon Tentarelli, M. Catarina Silva |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Time Factors Cell General Physics and Astronomy mTORC1 0302 clinical medicine Neural Stem Cells Phagosomes Medicine lcsh:Science Neurons Multidisciplinary biology Drug discovery TOR Serine-Threonine Kinases Middle Aged Cell biology Phenotype medicine.anatomical_structure Tauopathies Female Tauopathy Cell Survival Science Tau protein tau Proteins Mechanistic Target of Rapamycin Complex 1 Models Biological Article General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Downregulation and upregulation Stress Physiological Autophagy Animals Humans Rats Wistar Neurodegeneration Protein Kinase Inhibitors business.industry General Chemistry medicine.disease 030104 developmental biology biology.protein lcsh:Q Lysosomes business 030217 neurology & neurosurgery Ex vivo |
| Zdroj: | Nature Communications, Vol 11, Iss 1, Pp 1-18 (2020) Nature Communications |
| ISSN: | 2041-1723 |
| DOI: | 10.1038/s41467-020-16984-1 |
| Popis: | Tauopathies are neurodegenerative diseases associated with accumulation of abnormal tau protein in the brain. Patient iPSC-derived neuronal cell models replicate disease-relevant phenotypes ex vivo that can be pharmacologically targeted for drug discovery. Here, we explored autophagy as a mechanism to reduce tau burden in human neurons and, from a small-molecule screen, identify the mTOR inhibitors OSI-027, AZD2014 and AZD8055. These compounds are more potent than rapamycin, and robustly downregulate phosphorylated and insoluble tau, consequently reducing tau-mediated neuronal stress vulnerability. MTORC1 inhibition and autophagy activity are directly linked to tau clearance. Notably, single-dose treatment followed by washout leads to a prolonged reduction of tau levels and toxicity for 12 days, which is mirrored by a sustained effect on mTORC1 inhibition and autophagy. This new insight into the pharmacodynamics of mTOR inhibitors in regulation of neuronal autophagy may contribute to development of therapies for tauopathies. Disruption of autophagy function in cellular and animal models of tauopathy increases tau aggregation. Here, the authors describe a small-molecule screen to identify compounds that promote autophagy clearance of tau and rescue disease-relevant phenotypes in tauopathy patient-derived neurons. |
| Databáze: | OpenAIRE |
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