Research Paper Volume 8, Issue 12 pp 3507—3519
TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin
- 1 Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School at Houston, Houston, TX 77030, USA
- 2 The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
- 3 Department of Neuro-Oncology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
- 4 Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA
- 5 Department of Gynecologic Oncology and Reproductive Medicine, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
- 6 Center for RNA Interference and Non-Coding RNA, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
- 7 Department of Cancer Biology, the University of Texas, MD Anderson Cancer Center, Houston, TX 77030, USA
Received: September 5, 2016 Accepted: December 12, 2016 Published: December 16, 2016
https://doi.org/10.18632/aging.101144How to Cite
Abstract
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.