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Title: Autophagy upregulation by the TFEB inducer trehalose protects against oxidative damage and cell death associated with NRF2 inhibition in human RPE cells
Authors: Abokyi, S 
Shan, SW 
To, CH 
Chan, HHL 
Tse, DYY 
Issue Date: 22-Jul-2020
Source: Oxidative medicine and cellular longevity, 22 July 2020, v. 2020, 5296341, p. 1-18
Abstract: Trehalose is a natural dietary molecule that has shown antiaging and neuroprotective effects in several animal models of neurodegenerative diseases. The role of trehalose in the management of age-related macular degeneration (AMD) is yet to be investigated and whether trehalose could be a remedy for the treatment of diseases linked to oxidative stress and NRF2 dysregulation. Here, we showed that incubation of human retinal pigment epithelial (RPE) cells with trehalose enhanced the mRNA and protein expressions of TFEB, autophagy genes ATG5 and ATG7, as well as protein expressions of macroautophagy markers, LC3B and p62/SQTM1, and the chaperone-mediated autophagy (CMA) receptor LAMP2. Cathepsin D, a hydrolytic lysosomal enzyme, was also increased by trehalose, indicating higher proteolytic activity. Moreover, trehalose upregulated autophagy flux evident by an increase in the endogenous LC3B level, and accumulation of GFP-LC3B puncta and free GFP fragments in GFP-LC3 boxed times expressing cells in the presence of chloroquine. In addition, the mRNA levels of key molecular targets implicated in RPE damage and AMD, such as vascular endothelial growth factor- (VEGF-) A and heat shock protein 27 (HSP27), were downregulated, whereas NRF2 was upregulated by trehalose. Subsequently, we mimicked in vitro AMD conditions using hydroquinone (HQ) as the oxidative insult on RPE cells and evaluated the cytoprotective effect of trehalose compared to vehicle treatment. HQ depleted NRF2, increased oxidative stress, and reduced the viability of cells, while trehalose pretreatment protected against HQ-induced toxicity. The cytoprotection by trehalose was dependent on autophagy but not NRF2 activation, since autophagy inhibition by shRNA knockdown of ATG5 led to a loss of the protective effect. The results support the transcriptional upregulation of TFEB and autophagy by trehalose and its protection against HQ-induced oxidative damage in RPE cells. Further investigation is, therefore, warranted into the therapeutic value of trehalose in alleviating AMD and retinal diseases associated with impaired NRF2 antioxidant defense.
Publisher: Hindawi Publishing Corporation
Journal: Oxidative medicine and cellular longevity 
ISSN: 1942-0900
EISSN: 1942-0994
DOI: 10.1155/2020/5296341
Rights: Copyright © 2020 Samuel Abokyi et al. This is an open access article distributed under the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The following publication Abokyi, S., Shan, S. W., To, C. H., Chan, H. H. L., & Tse, D. Y. Y. (2020). Autophagy upregulation by the TFEB inducer trehalose protects against oxidative damage and cell death associated with NRF2 inhibition in human RPE cells. Oxidative Medicine and Cellular Longevity, 2020, 1-18 is available at https://dx.doi.org/10.1155/2020/5296341
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