Medical College of Wisconsin
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TFEB ameliorates the impairment of the autophagy-lysosome pathway in neurons induced by doxorubicin. Aging (Albany NY) 2016 Dec 16;8(12):3507-3519

Date

12/20/2016

Pubmed ID

27992857

Pubmed Central ID

PMC5270683

DOI

10.18632/aging.101144

Scopus ID

2-s2.0-85010589813 (requires institutional sign-in at Scopus site)   51 Citations

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.

Author List

Moruno-Manchon JF, Uzor NE, Kesler SR, Wefel JS, Townley DM, Nagaraja AS, Pradeep S, Mangala LS, Sood AK, Tsvetkov AS

Author

Sunila Pradeep PhD Associate Professor in the Obstetrics and Gynecology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Autophagosomes
Autophagy
Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
Cells, Cultured
Doxorubicin
Female
Gene Expression Regulation
Lipid Droplets
Lysosomes
Mice
Mice, Nude
Neurons
Rats
Sequestosome-1 Protein
Topoisomerase II Inhibitors