Dysregulated autophagy in the RPE is associated with increased susceptibility to oxidative stress and AMD.

Published

Journal Article

Autophagic dysregulation has been suggested in a broad range of neurodegenerative diseases including age-related macular degeneration (AMD). To test whether the autophagy pathway plays a critical role to protect retinal pigmented epithelial (RPE) cells against oxidative stress, we exposed ARPE-19 and primary cultured human RPE cells to both acute (3 and 24 h) and chronic (14 d) oxidative stress and monitored autophagy by western blot, PCR, and autophagosome counts in the presence or absence of autophagy modulators. Acute oxidative stress led to a marked increase in autophagy in the RPE, whereas autophagy was reduced under chronic oxidative stress. Upregulation of autophagy by rapamycin decreased oxidative stress-induced generation of reactive oxygen species (ROS), whereas inhibition of autophagy by 3-methyladenine (3-MA) or by knockdown of ATG7 or BECN1 increased ROS generation, exacerbated oxidative stress-induced reduction of mitochondrial activity, reduced cell viability, and increased lipofuscin. Examination of control human donor specimens and mice demonstrated an age-related increase in autophagosome numbers and expression of autophagy proteins. However, autophagy proteins, autophagosomes, and autophagy flux were significantly reduced in tissue from human donor AMD eyes and 2 animal models of AMD. In conclusion, our data confirm that autophagy plays an important role in protection of the RPE against oxidative stress and lipofuscin accumulation and that impairment of autophagy is likely to exacerbate oxidative stress and contribute to the pathogenesis of AMD.

Full Text

Duke Authors

Cited Authors

  • Mitter, SK; Song, C; Qi, X; Mao, H; Rao, H; Akin, D; Lewin, A; Grant, M; Dunn, W; Ding, J; Bowes Rickman, C; Boulton, M

Published Date

  • 2014

Published In

Volume / Issue

  • 10 / 11

Start / End Page

  • 1989 - 2005

PubMed ID

  • 25484094

Pubmed Central ID

  • 25484094

Electronic International Standard Serial Number (EISSN)

  • 1554-8635

Digital Object Identifier (DOI)

  • 10.4161/auto.36184

Language

  • eng

Conference Location

  • United States