TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin
| Autor: | Debra M. Townley, Sunila Pradeep, Shelli R. Kesler, Anil K. Sood, Ndidi-Ese Uzor, Lingegowda S. Mangala, Andrey S. Tsvetkov, Jose F. Moruno-Manchon, Archana S. Nagaraja, Jeffrey S. Wefel |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
autophagy Aging Mice Nude Mitochondrion chemotherapy doxorubicin Lipofuscin Mice 03 medical and health sciences 0302 clinical medicine Lipid droplet Lysosome Sequestosome-1 Protein polycyclic compounds medicine Animals Topoisomerase II Inhibitors Doxorubicin Cells Cultured Neurons TFEB Basic Helix-Loop-Helix Leucine Zipper Transcription Factors Chemistry Autophagy Autophagosomes Neurotoxicity Lipid Droplets Cell Biology medicine.disease Rats 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation 030220 oncology & carcinogenesis Female brain aging Lysosomes Research Paper medicine.drug |
| Zdroj: | Aging (Albany NY) |
| ISSN: | 1945-4589 |
| DOI: | 10.18632/aging.101144 |
| Popis: | Doxorubicin, a commonly used chemotherapy agent, induces severe cardio- and neurotoxicity. Molecular mechanisms of cardiotoxicity have been extensively studied, but mechanisms by which doxorubicin exhibits its neurotoxic properties remain unclear. Here, we show that doxorubicin impairs neuronal autophagy, leading to the accumulation of an autophagy substrate p62. Neurons treated with doxorubicin contained autophagosomes, damaged mitochondria, and lipid droplets. The brains from mice treated with pegylated liposomal doxorubicin exhibited autophagosomes, often with mitochondria, lipofuscin, and lipid droplets. Interestingly, lysosomes were less acidic in doxorubicin-treated neurons. Overexpression of the transcription factor EB (TFEB), which controls the autophagy-lysosome axis, increased survival of doxorubicin-treated neurons. 2-Hydroxypropyl-β-cyclodextrin (HPβCD), an activator of TFEB, also promoted neuronal survival, decreased the levels of p62, and lowered the pH in lysosomes. Taken together, substantial changes induced by doxorubicin contribute to neurotoxicity, cognitive disturbances in cancer patients and survivors, and accelerated brain aging. The TFEB pathway might be a new approach for mitigating damage of neuronal autophagy caused by doxorubicin. |
| Databáze: | OpenAIRE |
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